Skip to main content

Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management


Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.


Chemotherapy and targeted therapy are mainstream cancer treatments, but their efficiency is limited by frequent drug resistance and tumor relapse [1,2,3]. Generally, cancer drug resistance can result from two types of mechanism: intrinsic or acquired causes [4,5,6,7,8]. Intrinsic resistance is due to preexisting resistance-mediating factors prior to any treatment administered, while acquired drug resistance is caused by adaptive responses that confer cancer cell survival in unfavorable environments during drug treatment [9,9,10,12]. These adaptive response mechanisms include reduced uptake of drugs or increased drug efflux, ineffective induction of cell death, and compensatory activation of pro-survival signaling pathways [13,13,15]. Moreover, it is increasingly recognized that drug resistance can generally arise from a minor resistant subpopulation of cancer cells due to the high incidence of tumor heterogeneity. Recent studies have demonstrated that cancer stem cells (CSCs) are prone to maintain a quiescent state to evade the drug cytotoxicity which contributes to the development of a whole resistance phenotype [16,17,18,19]

Cancer cells often reprogram their metabolic pathways to provide energetic and biosynthetic flexibility to survive in hostile conditions when exposed to cancer treatments [2026]. Metabolic reprogramming is considered as one of the major hallmarks of cancer [27] and has been an area of accelerated research over the last century on the basis of aerobic glycolysis theory proposed by Otto von Warburg, which describes the preference for glycolysis by tumors in the presence of oxygen [28,26,27,28,29,30,31,32,33,37]. While numerous studies have well documented the crucial role of metabolic adaptations in supporting cancer progression under endogenous stress such as hypoxia, cancer cells also develop metabolic flexibility to survive in response to exogenous stress including drug administration [28, 38,36,40]. Chemoresistance caused by glucose metabolic plasticity, for example, is generally mediated by several key glycolytic factors, such as Hexokinase 2 (HK2), glucose transporter 1 (GLUT1), as well as pyruvate kinase isozymes M2 (PKM2) [41,39,40,44]. The augmentation of glycolysis results in enhanced secretion of lactate and production of glycolytic intermediates, which activate branching pathways (e.g., pentose phosphate pathway (PPP)) and the stress response machinery to support nucleotide synthesis and redox homeostasis, leading to escape from apoptosis and reduction in drug entry [45, 46]. Correspondingly, targeting the dynamic adaptability of metabolism has obtained considerable effect in improving the efficiency of cancer therapy [47,45,46,50].

Mitochondria are the major organelles that provide bioenergetic and biosynthetic changes, which accompany tumor progression by taking up substrates from the cytoplasm to drive the electron transport chain (ETC) and respiration, the tricarboxylic acid cycle (TCA cycle), fatty acid oxidation (FAO), and subsequent macromolecule synthesis (Fig. 1) [51,49,50,54]. Additionally, mitochondria can rapidly sense and adapt to stress stimulation to ensure cell survival. Advanced studies on cancer metabolism have expanded our understanding of mitochondrial metabolic alterations to support anabolic requirements of cancer cells, which depend largely on the strictly intertwined plasticity of mitochondria (mitochondrial dynamics), including fusion/fission, trafficking/transfer, and inter-organelle communication/retrograde signaling [55]. While participating in the maintenance of cellular homeostasis during tumor progression, these mitochondrial adaptive processes are also pivotal for handling drug-induced stress, which contributes to alterations in mitochondrial metabolism and subsequent drug resistance [56,54,55,59]. For example, mitochondrial fission provides an advantage for cisplatin-resistant cells compared with their nonresistant counterpart under hypoxic conditions in ovarian cancer [60, 61]. In melanoma, the increased oxidative phosphorylation (OXPHOS) in resistant subclones is supported by peroxisome proliferator-activated receptorγcoactivator-1 (PGC-1α) and is required for buffering oxidative stress [46]. Indeed, mitochondria have received increasing attention as a therapeutic target for cancer therapy, and several agents targeting mitochondrial metabolism are under investigation [62,60,64]. However, the dynamic alterations and inaccessible characteristics of mitochondria make it a priority to explore novel mitochondria-targeting agents and strategies.

Fig. 1
figure 1

Mitochondria are energetic and biosynthetic signaling hubs. Mitochondria take up substrates from the cytoplasm to provide bioenergetic and biosynthetic flexibility. The TCA cycle coordinates glycolysis and glutaminolysis to provide blocks necessary for macromolecule (nucleotides, lipids, and amino acids) synthesis. This process produces ATP, NADPH, as well as the electron donors in OXPHOS (NADH and FADH2). The ETC complexes produce the majority of cellular ATP and oxidize NADH and FADH2 to NAD+ and FAD, respectively, to allow the oxidative TCA cycle to continuously function, producing metabolites that support macromolecule synthesis. DHODH couples de novo pyrimidine synthesis to donate electrons to mitochondrial ubiquinone (CoQ) during the conversion of dihydroorotate to orotate. Mitochondrial dynamics facilitate maximum survival advantages of cancer cells in response to stress by maintaining mitochondrial metabolism, ion homeostasis such as Ca2+ signaling, and redox balance

Here, we address the most recent findings regarding mitochondrial dynamics to indicate their functions in cancer drug resistance. An overview of existing mitochondrial agents will be presented, and emerging strategies for effective tumor elimination by targeting mitochondria, including drug repurposing and mitochondrial-targeted drug delivery systems, will be summarized.

Mitochondrial structure and functions

Mitochondria are one of the most evolutionary conserved intracellular organelles that consist of the outer mitochondrial membrane (OMM) and a highly folded inner mitochondrial membrane (IMM) [65]. These two membranes are separated by the mitochondrial intermembrane space (IMS) and differ from each other in lipid composition and permeability. Importantly, the IMM invaginates into the mitochondrial matrix to form cristae, the crucial structure for mitochondrial function [66]. To maintain these structures, mitochondria undergo multiple complex processes (including fission and fusion) to dynamically control the function of mitochondria under various stimuli [67].

The primary function of mitochondria is demonstrated as energy supply. During the process of energy production, mitochondria integrate several metabolic pathways, including TCA cycle, FAO, amino acid oxidation, OXPHOS, etc., to provide not only most of the cellular ATP but also intermediate metabolite, supporting multiple physiological functions of the organism [68]. In recent decades, numerous studies have demonstrated that mitochondria also function as a signaling organelle to participate in many physiological processes, such as Ca2+ homeostasis, redox homeostasis, apoptosis regulation, and synthesis of heme and iron–sulfur clusters [69]. Indeed, mitochondria regulate Ca2+ homeostasis by exporting Ca2+ absorbed from intracellular store or extracellular uptake, which release Ca2+ back to the cytosol for regulation of calcium-dependent signaling [70]. In addition, the by-products of electron transfer during mitochondrial respiration result in the generation of reactive oxygen species (ROS), in which complexes I and III play the central role [71]. These physiological ROS together with the reducing equivalents (NADPH, etc.) generated by mitochondrial metabolism maintain the redox homeostasis for normal biological functions [72]. Moreover, mitochondria are tightly associated with apoptosis induction, as the release of cytochrome c, the key event of intrinsic apoptotic pathway, is mediated by the mitochondrial outer membrane permeabilization (MOMP) [73]. Therefore, the above complicated functions of mitochondria require the sophisticated regulation of mitochondrial dynamics for maintaining normal physiological functions of the organism.

Mitochondrial defects caused by various stimuli may lead to various pathologies, including neurodegenerative diseases, aging, and especially cancer. A large number of studies have suggested that mitochondria dysfunction may promote cancer onset and progression mainly through the following crucial mechanisms. First, as mitochondria are the major source of intracellular ROS, adequate levels of reactive species not only enable the accumulation of oncogenic defects of genes but also favor the activation of several oncogenic signaling pathways, which result in aberrant cell proliferation [74]. In addition, metabolic pathways in mitochondria may lead to the abnormal accumulation of specific metabolites, such as α-ketoglutarate (α-KG), pyruvate, fumarate, and succinate, which display significant oncogenic role during cancer initiation and progression [75,73,74,78]. Moreover, alterations or functional defects in MOMP are beneficial for survival of tumor cells when facing harsh conditions (such as hypoxic stress, metabolic stress, and therapeutic stress), thereby resisting regulated cell death [79]. During the dissemination and colonization, mitochondria endow metastatic cancer cells with phenotypic and metabolic plasticity for survival in intravascular transit and distant sites [80]. Taken together, the complex structures confer the diverse functions of mitochondria, whose dysfunction may regulate several aspects of cancer onset and progression, indicating a promising therapeutic target.

Mitochondrial stress adaptation and drug resistance

Mitochondrial metabolic plasticity contributes to resistance in most types of anticancer therapy, as emphasized above [81, 82]. It is well orchestrated as a prerequisite of maintenance of OXPHOS, balance of ROS for signaling or defense, Ca2+ homeostasis, and proper induction of the apoptotic cascade. Mitochondrial dynamics modulate their shape, number, quality, and distribution in response to treatment and allow the maintenance of functional mitochondria (Fig. 2) [83]. Mitochondrial biogenesis and turnover, fusion and fission are universal mitochondrial stress-adaptive processes and have been well demonstrated to be involved in cancer drug resistance. Recent advances have expanded the paradigm of mitochondrial dynamics into mitochondrial trafficking and transfer, mitochondrial interplay with other organelles, and mitochondrial retrograde signaling [55, 84, 85]. These processes provide mitochondria plasticity for tumor cells, enabling tumor cells to survive under stress conditions, including radiotherapy and chemotherapy. In addition, the membrane system is essential for mitochondrial integrity to make the mitochondrial network more efficient in providing energy and required macromolecules. In this section, we systematically review the engagement of mitochondrial dynamics in cancer drug resistance.

Fig. 2
figure 2

Mitochondrial stress adaptation and drug resistance. Mitochondrial dynamics are processes related to mitochondrial stress adaptation. These processes maintain proper mitochondrial numbers, structure, and position to ensure their function and could foster cancer drug resistance. (A) Fusion and fission allow mitochondria to constantly form networks or fragments according to cellular metabolic requirements. Mitophagy has been shown to coordinate with fission, facilitating the elimination of excessive or defective mitochondria. (B) While mitochondrial biogenesis and functions are largely regulated by nuclear coding factors, recent advances have revealed that mitochondrial dysfunction activates retrograde (mitochondria-to-nucleus) signaling to modify nuclear gene expression and subsequent cell behavior. This mitochondrial retrograde signaling functions as an adaptive mechanism for tumor cells to sense and mitigate mitochondrial stress. (C) Reshaping, localization, and motility of mitochondria along the microtubules facilitate mitochondria tethering with the ER or other organelles. (D) Recently described nanotunnel formation promotes component exchange and transfer of intercellular mitochondria, which usually increase OXPHOS output and ATP production of recipient cells and confer them with a survival advantage

Mitochondrial biogenesis and turnover in drug resistance

Mitochondrial biogenesis and turnover are two opposing processes that work in concert to regulate mitochondrial mass, function, and quality regulating the biogenesis of new mitochondria and the removal of damaged mitochondria in a time-dependent manner. Mitochondrial biogenesis is regulated by the coordinated transcription of mitochondrial nuclear genes, in which PGC-1α plays a central regulatory role [86]. Reduced cellular bioenergetic output usually triggers mitochondrial biogenesis by activating AMPK to furnish OXPHOS and ATP production. In addition, oncogenes such as K-Ras and C-Myc are also involved in regulating mitochondrial biogenesis and increasing intracellular biosynthesis and respiration, thereby promoting tumorigenesis [87]. In particular, c-Myc controls the transcription of approximately 400 mitochondrial-related genes, thus regulating mitochondrial biogenesis [88]. These transcription networks provide metabolic flexibility for cancer cells to facilitate their adaptation to a hostile microenvironment and ultimately reduce the effectiveness of tumor treatment.

The most well-studied regulator involved in tumor drug resistance is PGC-1α, which facilitates tumor cell survival and metastasis under environmental stress by mediating mitochondrial biogenesis and OXPHOS [89, 90, 92]. Previous studies found that mutations in B-Raf or N-Ras in melanoma confer chemoresistance to MEK inhibitors by switching the metabolic mode to OXPHOS through upregulating PGC-1α or TFAM (transcription factor A, mitochondrial) to meet their bioenergy requirements [91, 93]. Similarly, upregulation of mitochondrial biogenesis and OXPHOS could augment tolerance to stimuli such as radiotherapy and ultraviolet radiation [94]. These studies demonstrate the critical role of adaptive mitochondrial biogenesis in drug-resistant capacity and highlight the potential of targeting mitochondrial OXPHOS for improving drug efficacy.

The maintenance of mitochondrial quality is also ensured by mitophagy, a programmed degradative process for eliminating excessive or defective mitochondria. Generally, the “eat me” signal on damaged mitochondria directly triggers mitophagy machinery by membrane depolarization and a cascade of phosphorylation and ubiquitination events to remove cytotoxic cellular components and maintain energy balance in the cell. It shares a common core mechanism with macro-autophagy but depends on specific mitophagy receptors, including the classical PTEN-induced putative kinase 1 (PINK1)-Parkin pathway [95, 96], and several other receptors, including Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3/NIX), FUN14 domain-containing protein 1 (FUNDC1), and Bcl-2-like protein 13 (BCL2L13). While these receptors have been well demonstrated to elicit mitophagy and facilitate tumor progression [97,94,99], they were proven to confer resistance of cancer cells to a variety of commonly used chemotherapy drugs, such as 5-fluorouracil (5-fu), cisplatin, and doxorubicin (Dox), by triggering mitophagy [64, 100, 101]. For example, the highly activated ATAD3A-PINK1/Parkin signaling pathway under hypoxic conditions confers tolerance of liver cancer cells to sorafenib [102]. In esophageal squamous cell carcinoma (ESCC) patients, PINK1-mediated mitophagy promotes tumor cell survival under neoadjuvant therapy [103]. Interestingly, PINK1 could recruit ARIH1, rather than Parkin, to trigger mitophagy and ultimately lead to drug resistance in breast and lung cancer cells [104]. Several other emerging receptors, such as FUNDC1 and Galectin-1, have been reported to be upregulated to promote resistance to cisplatin and ionizing radiation by eliciting mitophagy [105]. In addition, the upregulation of these receptors relies on a series of stress-adaptive transcriptional programs mediated by p53, NF-κB, and STAT1/2 [106]. It would be of interest to further explore the regulatory role of these networks in regulating mitophagy and their potential role in drug resistance.

Mitochondrial fusion and fission in drug resistance

Mitochondrial fusion and fission allow mitochondria to constantly form networks or fragments according to cellular metabolic requirements. In general, fusion is commonly triggered by huge energy requirements, mediated by dynamin-related GTPases, optic atrophy 1 (OPA1) for IMM and mitofusin (MFN) 1 and 2 for OMM, resulting in a hyperfused mitochondrial network with increased mtDNA integrity, mitochondrial respiration, ATP production, and mitochondrial membrane potential (MMP) [107, 108]. Mitochondrial fission is mainly mediated by dynein-related protein 1 (DRP1) and fission protein homologous protein 1 (FIS1) and has been shown to coordinate with mitophagy or apoptosis, facilitating the elimination of damaged mitochondria, the redistribution of mtDNA, and the mobility of mitochondria [109,106,107,108,113]. These two opposing processes are tightly organized in response to stressors, thus engaging in tumor progression in a context-dependent manner [114,111,116]. For instance, the increase in mitochondrial fission caused by hypoxia has been shown to enhance the invasion of breast cancer [117].

Recent advances in mitochondrial medicine highlight the engagement of mitochondrial fusion and fission in mediating metabolic adaptation to chemotherapeutic agents in tumor cells. The relevance of mitochondrial fusion in chemoresistance is primarily evidenced by the upregulation of OPA1 and MFN1/2 expression, as well as interconnected mitochondrial networks in drug-resistant cancer cells. For instance, upregulated OPA1 confers resistance to cytochrome c release upon prolonged venetoclax treatment in acute myeloid leukemia (AML) cells [118]. Consistently, upregulated MFN2 and increased OXPHOS have been found in cancer cells that survive chemotherapy [119, 120]. Several other factors have been reported to promote cancer drug resistance by triggering mitochondrial fusion. For example, circulating leptin protein activates induced myeloid leukemia cell differentiation protein (MCL1, a member of the anti-apoptotic protein BCL2 family) to induce mitochondrial fusion, thereby promoting tumor cells to survive during gemcitabine treatment [121].

Increasing evidence also shows the pivotal role of mitochondrial fission in chemoresistance [60, 122]. One of the best examples is that phosphorylation of DRP1 induces mitochondrial fragmentation to promote metabolic adaptation, thus protecting cancer cells from chemotherapy agents [123,120,125]. Phosphorylation or activation of several upstream kinases, such as AMPK, cyclin B1/Cdk1, ERK1, and DRP1, is involved in mitochondrial fission-mediated chemoresistance [61, 126]. Since mitochondrial fusion and fission represent two opposing systems, their balance and role in cellular fate are carefully orchestrated by specific cellular metabolic requirements. Therefore, more insights into the regulatory patterns of mitochondrial fusion and fission and their effect in chemotherapy are necessary to develop therapies offering improved clinical outcomes for cancer patients.

Inter-organelle contact sites, mitochondrial trafficking, and transfer in drug resistance

Mitochondria dynamically form contacts with various intracellular organelles to maintain cell homeostasis by fine-tuning Ca2+ transfer, phospholipid biosynthesis, ROS signaling, mitochondrial quality control, and mtDNA synthesis [127,124,125,126,127,128,133]. Such cellular membrane interactions are extensive and play the essential role in cell adaptation to metabolic stress [134].

The mitochondrial-associated endoplasmic reticulum (ER) membrane (MAM) is the most well-studied membranous system coordinating with a series of proteins and factors to maintain proper mitochondrial Ca2+ uptake which correlates with resistance to chemotherapy [135]. Mitochondrial Ca2+ uniporter complex (MCUC) subunits (MCU, MICU1, MICU2, EMRE, and MCUb) cooperate to maintain mitochondrial Ca2+ homeostasis, and their relevance to drug resistance is condition dependent [136,133,134,139]. For example, downregulation of MCU was demonstrated to confer resistance by restricting the transport of Ca2+ to the mitochondria in HeLa cells [140]. However, the interaction of MCU with receptor-interacting protein kinase 1 (RIPK1) can increase mitochondrial Ca2+ uptake, resulting in increased proliferation of colorectal cancer cells [141]. Additionally, MCUR1-mediated mitochondrial Ca2+ signaling was reported to facilitate cell survival of hepatocellular carcinoma (HCC) upon pro-apoptotic stimuli [137]. Several other recognized mitochondrial proteins, such as MFN2 and voltage-dependent anion-selective channel proteins (VDACs), were identified as important MAM proteins that might be involved in tethering MAMs and facilitating mitochondrial fission, mitophagy, and mitochondrial positioning [142, 143]. Moreover, there is mitochondrial contact with other organelles, such as peroxisomes, and lipid droplets, in response to metabolic stress. For example, “lipid droplet mitochondria” can help mitochondria provide energy by burning fatty acids (FAs) to support the TCA cycle [144]. Therefore, we conclude that exploring mitochondria-associated tethering systems could expand the understanding of mitochondrial dynamics and provide new targets for tumor intervention.

The proper localization of organelles is often crucial to their activity and function [145]. Numerous studies have shown that the movement and subcellular location of mitochondria can affect tumor cell polarity, morphology, and mobility capacity [146,143,144,145,150]. Mitochondrial stress responses drive strategic mitochondrial redistribution to fulfill bioenergetic needs, Ca2+ homeostasis, ROS buffering, and signal transduction, thus promoting the adaptation of tumor cells to the harsh tumor microenvironment [150,147,148,149,150,151,156]. A typical example is that of mitochondria migrating to the invasive front of metastatic tumor cells [157]. For example, the NF-κB-inducing kinase (NIK)-DRP1 axis could mediate the fission and subsequent directionally positioning of mitochondria to the cell periphery to promote the migration of a variety of tumors [151, 158]. In addition, the trafficking of mitochondria along the cytoskeleton could protect cells from detrimental ROS production [155, 159]. Notably, mitochondrial trafficking occurs to endow tumor cells for survival and metastasis upon drug abuse [160]. For instance, activated Akt promotes mitochondria positioning along the cytoskeleton to provide an effective “regional” energy source, thus fueling resistance and even adaptive cell invasion in response to PI3K inhibitors [148]. Intensive studies on this “spatiotemporal” model of mitochondria may deepen our understanding of the subcellular accumulation of mitochondria as an adaptative process and may provide a viable strategy to increase anticancer efficacy in the clinic.

Recent studies have shown that mitochondrial dynamics are accompanied by intercellular mitochondrial transfer [161,158,163]. This transfer process is achieved through several mechanisms, including gap junctions, extracellular vesicles (EVs), and tunneling nanotubes (TNTs) [164,161,162,163,164,169]. TNTs, the transient cytoplasmic extensions, are the major cellular structure that mediate intercellular mitochondrial transfer [170]. The mitochondrial transfer process usually increases the OXPHOS output and ATP level of recipient cells. As a consequence, recipient cancer cells exhibit a survival advantage and resistance to stress [171,168,173]. Moschoi et al. observed that AML cells acquire intact mitochondria from marrow stromal cells (MSCs) to maintain their own mitochondrial function and survive during cytarabine treatment [174]. Several other tumors can also despoil mitochondria from MSCs and obtain resistance to chemotherapeutics [172]. In addition, it has been proposed that mitochondria transfer from bone marrow stromal cells (BMSCs) to multiple myeloma (MM) cells, which can also contribute to chemoresistance [175, 176]. Consistently, in breast cancer, mitochondrial transfer promotes resistance to doxorubicin [177], and mtDNA in exosomes derived from hormonal therapy-resistant breast cancer cells leads to endocrine therapy resistance. Intercellular transfer of mitochondria expands the influence of mitochondria on tumor metabolism, suggesting that targeting mitochondrial transfer could represent a more reasonable and effective antitumor strategy.

Mitochondrial retrograde signaling in drug resistance

Mitochondrial dynamic changes are positively regulated by nuclear coding factors, while recent advances underline that retrograde signaling activated by mitochondrial dysfunction can modify nuclear gene expression and subsequent cell behavior [59, 178]. In fact, it serves as an adaptive mechanism for tumor cells to sense and mitigate mitochondrial stress, thus participating in tumor survival, metastasis, and drug resistance.

Retrograde reactions

The signals from mitochondrial dysfunction, especially mutation/deletion in mtDNA, are usually relayed to the nucleus by TCA cycle intermediates, ATP, Ca2+ or ROS, which activate specific kinases to initiate transcriptional regulation of nuclear genes or posttranslational modification of key proteins (e.g., histone acetylation) [179,176,181]. The most well-studied example is the activation of AMPK triggered by a decrease in ATP levels, which elicits PGC-1α-mediated transcription of genes responsible for energy metabolism, mitochondrial synthesis, and the quality control system [182, 183].

As mentioned above, mitochondria are essential for maintaining intracellular Ca2+ levels. Disruption of MMP caused by deletion of the electron transport chain complex or drug insult led to leakage of Ca2+ into the cytoplasm. Intracellular free Ca2+, on the one hand, activates multiple oncogenic signaling pathways, including RAC-alpha serine/threonine-protein kinase (AKT) and phosphatidylinositol 3-kinase (PI3K), to upregulate the expression of glucose transporters, such as GLUT1 and GLUT4, thereby promoting the metabolic switch to glycolysis and the survival of cancer cells [184,181,186]. On the other hand, Ca2+ signaling activates NF-κB and T cell nuclear factor (NFATC) signaling to facilitate the transcription of Ca2+ transport and storage-related proteins [187, 188].

ROS can directly manipulate cellular redox homeostasis and act as second messengers to regulate cellular physiological and pathological processes [189,186,191]. For example, ROS elicited by mtDNA depletion could activate the NRF2 signaling pathway and the multidrug resistance proteins MRP1 and MRP2 to help tumor cells fight against ROS and survive under cisplatin, doxorubicin, and SN-38 treatment [192]. In addition, ROS modulate the expression of PGC-1α to promote OXPHOS, thus conferring cisplatin resistance in ovarian cancer cells [193]. Together, these studies have linked mtDNA mutations/deletion with changes in sensitivity of cancer cells to chemotherapy, thus providing a new perspective on modulating drug resistance.

Mitochondrial nuclear feedback and mitochondrial stress-relieving response

Mitochondria have evolved protein quality control systems to maintain mitochondrial integrity by ensuring proper folding, assembly, and circulation of mitochondrial proteins in response to exogenous or endogenous stressors. This process tightly relies on feedback regulatory loops, including the mitochondrial unfolded protein stress response (UPRmt) [194], proteolytic stress responses [195], and the heat shock response of mitochondrial chaperones [196]. These mechanisms are deregulated due to altered signaling to confer cancer cell survival, which ultimately contribute to tumor progression and drug resistance. This could be due to several proposed mechanisms, including continuous activation of NF-κB and molecular chaperone systems and mutations in the catalytic sites that contribute to resistance to proteasome inhibitors. For instance, a recent study has suggested that the mitochondrial oxidoreductase ferredoxin 1 (FDX1) maintains mitochondrial metabolism to promote the adaptation of tumor cells to the proteasome inhibitor elesclomol [197]. More investigations revealing the mechanisms employed in the quality control system of mitochondrial protein might offer unique strategies for improving therapeutic efficacy in cancer treatment.

Mitochondrial-derived peptides

Recently, mitochondria-derived peptides (MDPs, short open reading frames (sORFs) of mitochondrial genome) have been identified and implicated in stress response, metabolic regulation, and other biological processes. In response to cellular stress, these peptides can even directly manipulate nuclear gene expression [198], which expands the paradigm of mitochondrial nuclear communication. Several MDPs have been identified, including Humanin [199], humanin-like peptides (SHLP) 1–6 [200], and MOTS-c [201,198,203]. Among them, humanin was reported to protect cells from oxidative stress and mitochondrial dysfunction [204]. SHLP2 and SHLP3 exert similar cytoprotective effects by maintaining mitochondrial function and combating excessive ROS levels [202, 205]. In particular, MOTS-c was reported to translocate to the nucleus under metabolic stress such as glucose deprivation and oxidative stress [206]. In the nucleus, MOTS-c regulates the transcription of a broad range of genes, including those with antioxidant response elements (AREs) and other anti-inflammatory-associated genes, to initiate the stress adaptation program. A considerable number of studies have now proven that MDPs are intrinsically linked to tumor progression, and targeting MDPs holds potential to improve the efficacy of chemotherapeutics [207, 208].

Mitochondria-mediated CSC properties in drug resistance

It is well established that CSCs contribute substantially to the refractory features of cancer. Under pharmacological treatment, mitochondria function as a central hub to maintain the survival and self-renewal capacity of CSCs, resulting in drug resistance and tumor recurrence [209]. For example, it has been reported that oncogenic Myc cooperated with MCL1 to maintain chemoresistance of CSCs in triple-negative breast cancer (TNBC). Further studies found that Myc and MCL1 upregulated the levels of mitochondrial OXPHOS and promoted ROS generation, which contributed to the accumulation of HIF-1α and the subsequent maintenance of CSC properties [210]. Moreover, PGC-1α, a critical regulator of mitochondrial biogenesis, has been demonstrated to enhance stem cell-like characteristics and chemoresistance to cisplatin in ovarian cancer [211]. In addition, increased levels of mitochondrial mass were found in a subtype of chemo-resistant breast cancer cells enriching in several known CSC markers, implying the potential of targeting mito-high CSC population for cancer therapy [212]. Therefore, investigation of mitochondrial function in regulating CSCs holds the promise to benefit the development of novel CSC-targeted strategies for reversing cancer drug resistance.

In summary, a large body of evidence has indicated the important role of mitochondrial dynamics in the adaptative mechanism of cancer cells in response to a challenging environment, which is expected to expand the understanding of cancer drug resistance phenomena [91, 213,210,211,216]. Further investigations deciphering specific mitochondrial-related mechanisms implicated in the resistance could hopefully benefit the identification of possible biomarkers for the early prediction of cancer drug resistance and hold promise to target mitochondria for overcoming cancer drug resistance.

Targeting mitochondria to overcome cancer drug resistance: the current status and challenges

The mitochondrial ETC fuels cellular energy demands by utilizing intermediates from various metabolic pathways, including the TCA cycle and FAO, and couples the generation of macromolecules such as amino acids and nucleotides [217,214,219]. Thus, dynamic regulation of mitochondria involves robust metabolic and redox alterations, as well as changes in ion (e.g., Fe2+, Ca2+) homeostasis. Increasing knowledge that these critical processes are linked to tumor transformation makes mitochondria an attractive therapeutic target. In this section, we will summarize current mitochondrial therapeutic targets and their proposed inhibitors (Fig. 3, Table 1), with a particular emphasis on the role of small-molecule inhibitors in targeting mitochondria to overcome cancer chemoresistance.

Fig. 3
figure 3

Schematic showing representative mitochondrial therapeutic targets and their proposed inhibitors. The mitochondrial ETC, as the central system of mitochondrial energy production and OXPHOS, has been the most frequently used mitochondrial target. Multiple mitochondrial ETC inhibitors, including metformin and IACS-010759, are being investigated for cancer treatment. In addition, inhibitors targeting different steps of the mitochondrial TCA cycle have shown promise in phase I and II clinical trials. Several other TCA cycle-coupled biomacromolecule synthesis pathways, such as the nucleotide synthesis pathway and the one-carbon (1C) metabolic pathway, are also potential therapeutic targets for reversing drug resistance

Table 1 Summary of mitochondrial targets for cancer therapy

Targeting mitochondrial ETC

The mitochondrial ETC complexes I–V (hereafter CI-V) bypass electrons to generate energy and are the major source of mitochondrial ROS [250, 251]. Disruption of the ETC inevitably triggers apoptosis and perturbs the cellular redox balance and therefore provides a possible strategy for eliminating cancer cells [252].

Complex I

Mitochondrial complex I (CI), the largest complex of the ETC, transfers TCA cycle-derived electrons from NADH from the UbQ and maintains the proton gradient on the MIM. Several inhibitors including piericidin, tamoxifen, metformin, and ME-344 that directly target the respiratory complex I have gained momentum as potential antitumor therapeutics. Metformin, an antidiabetic drug has now been repurposed as an anticancer drug and was observed to inhibit CI. Many preclinical and clinical studies have demonstrated its excellent antitumor efficacy in managing resistance caused by chemotherapeutics, including cisplatin, Dox, and 5-FU (NCT00897884, NCT02437656; Table 2) [253,250,251,256]. In addition, a recent phase II clinical trial observed that combinational use of metformin with standard epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy significantly improved both progression-free survival and overall survival in patients with advanced lung adenocarcinoma (NCT03071705; Table 2) [257]. Consistently, metformin-sensitized lymphoma to isocitrate dehydrogenase (IDH) mutant inhibitors and increased the sensitivity of lymphoma to AZD3965, a monocarboxylate transporter (MCT1) inhibitor, by disturbing mitochondrial complex I and bioenergetics, thus providing a scientific rationale for combinatory mitochondrial-targeted therapies to overcome drug resistance in human lymphoma [53, 258].

Table 2 Clinical trials of identified mitochondrial inhibitors

Complex II

Complex II (CII, succinate dehydrogenase), the smallest respiratory complexes, is a membrane-bound component of the TCA cycle that permits the oxidation of succinate to fumarate. Compounds that induce substantial ROS generation from CII are the emerging anticancer drugs. For example, alpha-tocopheryl succinate (α-TOS), a compound targeting UbQ-binding sites in CII, has been demonstrated to disturb CII for eliciting mitochondrial permeabilization and apoptosis, thus showing significant potential in overcoming drug resistance in various tumors [226, 259, 260]. In particular, based on the knowledge that α-TOS targets UbQ-binding sites, a more specific mitochondrial-targeted analogue, MitoVES, was designed for efficiently suppressing tumors by disturbing mitochondria [261, 262].

Complex III

CIII, similar to CI, functions by pumping protons across the MIM and contributing to the proton gradient. It has been also identified as target for anticancer drugs. Antimycin A is the most classic CIII inhibitor to trigger apoptosis for effectively eliminating cancer cells [263, 264]. Resveratrol, a plant-derived polyphenol, exhibited considerable antitumor efficacy by efficiently inhibiting ETC complexes, especially CIII to induce apoptosis and disturb multiple cellular processes in primary and resistant cancer cells [265,262,267]. Importantly, the anticancer potential of resveratrol is being investigated in clinical trials for the treatment of colorectal, liver, and breast cancer (NCT0025633, NCT00433576, and NCT03482401; Table 2).

Complex IV

CIV ensures the final step of electron transport in ETC to maintain the proton gradient and mitochondrial membrane potential. Several compounds have been observed to modulate the mRNA or protein expression of CIV subunits and thereby induce apoptosis in tumor cells. Fenretinide (also named as N-(4-hydroxyphenyl) retinamide, 4-HPR) and its analogue are perhaps the most well-documented category to downregulate CIV by destabilizing the mRNA transcript [268], thereby inducing ROS-mediated apoptosis to combat tumors in both preclinical and clinical studies (NCT00004154, NCT00009971, and NCT00077402; Table 2) [269, 270]. In particular, Fenretinide has been reported to eliminate ABT-737-resistant cell lines via ROS generation and MCL1 reduction and thus has synergetic effect with ABT-737 to enhance mitochondrial apoptotic cascade in acute lymphoblastic leukemia (ALL) [271].

Complex V

CV, the ATP synthase, directly catalyzes ATP production using the proton gradient maintained by complexes I–IV, thus supplying the cell with essential energy. Besides oligomycin and its derivatives, several newly identified CV inhibitors, including 3,30-diindolylmethane (DIM), Bz-423, were proposed to fight tumors and even those with drug resistance [230, 272]. Notably, there are compounds that could inhibit different complexes of ECT. For example, resveratrol is also reported to bind to CV and induce Bcl-2-mediated apoptosis [273]. In addition, Gboxin, an OXPHOS inhibitor, is observed to interact with several respiratory chain proteins spanning CI, CII, CIV, and CV, thereby suppressing tumor growth [274]. Although it remains to be known whether these ETC inhibitors will be effective in humans, emerging studies provide excellent prospects for their application in cancer therapy and drug resistance eradication.

Mitochondrial redox balance

ROS are intrinsically involved in tumor progression by modulating cell survival, secondary signaling networks, and genetic instability/mutations [275]. Mitochondria function as a major contributor to endogenous ROS due to the large electron flow in the ETC and constant metabolism alterations involved in numerous enzyme-catalyzed reactions. Mitochondrial redox balance is typically mediated by cellular antioxidants, such as glutathione (GSH), glutathione peroxidases (GPx1 and GPx4), and glutathione reductase [276,273,274,275,276,277,282]. Emerging observations suggest that heightened levels of ROS contribute to drug resistance. For instance, gefitinib resistance was demonstrated to be associated with mitochondrial dysfunction in lung cancer cells [283]. Conventional chemotherapies, such as 5-FU and cisplatin, are designed to kill cancer cells via ROS-dependent mechanisms. In that context, enhanced ROS levels could maximize antitumor efficacy. For example, SMIP004-7 targets NADH:ubiquinone oxidoreductase to improve the immunotherapeutic effect of PD-1 in triple-negative breast cancer [242]. Destroying the redox balance is perhaps the essence for modulating mitochondrial ROS to benefit cancer therapy. In view of this, redox status during treatment and the basal mitochondrial ROS range may provide important clues for guiding rational intervention strategies. Selective targeting of ROS-specific organelles, as well as dynamic ROS delivery, might be beneficial for preventing drug resistance and effectively eliminating cancer cells.

Targeting the mitochondrial metabolic pathway

Nucleotide biosynthesis

Targeting mitochondrial ETC-linked metabolic pathways, such as nucleotide metabolism, also contributes to improved antitumor efficacy. One-carbon (1C) metabolism coordinates with serine synthesis to provide glycine and tetrahydrofolate methyl donors, namely methylene-THF (5,10-CH-THF) and formyl-THF (10-CHO-THF), for nucleotide synthesis. As essential enzymes in 1C metabolism, cytosolic SHMT1 and mitochondrial SHMT2 have attracted much attention. Several inhibitors, including AGF291, AGF320, and AGF347, have been developed to target these enzymes, and their antitumor efficacy has been established for lung, colon, and pancreatic cancer cells [233, 234, 284]. Intriguingly, folate inhibitors such as lometrexol have also been found to reduce SHMT1 and SHMT2 activity [235]. Several clinical trials are undergoing to investigate the use of lometrexol in advanced solid tumor (NCT00033722 and NCT00024310; Table 2).

In addition, efforts have been made to inhibit nucleotide metabolic enzymes, such as the intramitochondrial key pyrimidine synthesis-related enzyme, dihydroorotate dehydrogenase (DHODH). Leflunomide exhibited antitumor activity in prostate cancer mouse model by inhibiting DHODH [236]. Additionally, a phase I clinical study showed leflunomide had considerable activity toward myeloma with manageable side effects (NCT02509052; Table 2). Furthermore, IACS-010759, a mitochondrial CI inhibitor, was developed to induce apoptosis in brain cancer and AML, likely caused by energy depletion and reduced aspartate production that led to impaired nucleotide biosynthesis [238]. Combinational use of IACS-010759 with lactate dehydrogenase (LDH) inhibitor could overcome oxidative rewiring and show a synergistic therapeutic effect [49]. Key enzymes involving in nucleotide metabolism could also play a “part-time role” in other mitochondrial processes (e.g., SHMT2 participating in mitochondrial translation) [285,282,287]. The antitumor effects of nucleotide metabolism inhibitors could be manifold. As such, further efforts are urgently needed to screen for candidates targeting nucleotide metabolism for cancer management.

TCA cycle

The mitochondrial TCA cycle integrates multiple fuel sources to synthesize nucleotide, amino acid, lipid, and heme. Several TCA cycle inhibitors have been under investigation and predicted to be efficacious. Among them, CPI-613, a lipoate analog that targets two enzyme complexes of the TCA cycle (α-ketoglutarate dehydrogenase (α-KGDH) and pyruvate dehydrogenase (PDH)) [288], exerts anticancer activity in pancreatic cancer and AML [289]. Notably, CPI-613 could sensitize AML cells to cytarabine and mitoxantrone, representing a promising approach for relapsed or refractory AML [239]. To date, clinical trials of CPI-613 for the treatment of advanced or recurrent tumor are ongoing, or have already been completed with satisfactory results (NCT04203160, NCT01034475, and NCT01931787; Table 2). Interestingly, a recent study reported that vitamin C modulates the activity of PDH and regulates the TCA cycle via interfering with PDK1-mediated phosphorylation of PDH in KRAS mutant colon cancer, suggesting a potential application for clinical management of chemoresistance to anti-EGFR therapy [290].


Glutamine (Gln) can be converted to glutamate by glutaminase (GLS) and further metabolized to α-KG via glutamate dehydrogenase 1 (GLUD1), glutamate oxaloacetate transaminase 2 (GOT2) or glutamate-pyruvate transaminase 2 (GPT2), thus providing a major carbon source to replenish the TCA cycle [291,288,289,290,295]. Many classes of compounds that target mitochondrial Gln metabolism are being investigated for cancer treatment. GLS inhibitors have shown promising anticancer effect in preclinical models of cancer. For example, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES), a GLS inhibitor, has been demonstrated to slow the growth of various types of tumors [296, 297].

Importantly, BPTES was observed to efficiently sensitize pancreatic cancer to 5-(tetradecyloxy)-2-furoic acid (TOFA, an acetyl-CoA carboxylase inhibitor) and ß-Lap (an NADPH:quinone oxidoreductase (NQO1) inhibitor) via enhancing cancer cell apoptosis [241, 298, 299]. In particular, CB-839 (telaglenastat), another GLS inhibitor, has moved on to clinical trials and exhibits promise as potential drug for renal cell carcinoma (NCT03428217; Table 2), hematological malignancies (NCT03428217 and NCT02071888; Table 2), non-small cell lung cancer (NSCLC) (NCT02071862; Table 2), and even those drug-resistant tumors (NCT03944902 and NCT03798678; Table 2). Recently, GPT2 has been demonstrated to promote cell survival by supporting the TCA cycle after GLS inhibition [54]. In that context, inhibition of GPT2 using aminooxyacetate (AOA), a transaminase inhibitor, could thus sensitize cancer cells to BPTES.

Targeting Ca2+ homeostasis

Mitochondria have evolved Ca2+ influx and efflux systems to maintain cellular Ca2+ homeostasis. Proper mitochondrial Ca2+ ensures respiration efficacy and ATP production, while Ca2+ overload can induce mitochondria-mediated apoptosis [300,297,298,303]. Therefore, mitochondrial Ca2+ signaling pathways engage multifaceted roles in regulating cell fate and are beneficial for tumorigenesis. Studies are under way to identify the proteins involved in mitochondrial Ca2+ signaling pathways as alternative targets for cancer therapy, and to evaluate the potential for increasing the sensitivity toward chemotherapeutic treatment. Compounds that modulate mitochondrial porins such as VDACs and ANT, including lonidamine, arsenites, and steroid analogs, have been documented to disturb the mitochondrial Ca2+ balance and elicit mitochondrial apoptosis, thus showing potent antitumor efficacy as well as drug resistance overcoming activity [243, 244, 304]. In addition, a mitochondrial Na+/Ca2+ exchanger inhibitor, CGP-37157, resulted in a persistent mitochondrial Ca2+ rise and may serve as a promising agent to overcome TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) resistance [245, 303]. In ovarian cancer cells, the overexpression of Bcl-2 attenuated cisplatin cytotoxicity by downregulating ER-mitochondrial Ca2+ signal transduction. Thus, targeting Bcl-2-mediated Ca2+ signal might be a potential approach to overcome drug resistance in ovarian cancer [305].

Current challenges in targeting mitochondria

The mitochondrion is perhaps the most challenging target for cancer therapy [306, 307]. The constant alterations in mitochondrial structure and position contribute greatly to the failure of targeted agents, the bias in drug toxicity, and drug dosage prediction [308]. For example, the doses of metformin that could reduce the proliferation of cancer cells in laboratory models (in vitro cell lines and in vivo mouse models) were 10- to 1,000-fold higher than those that are deemed safe clinically [309]. This makes it urgent to assess the efficacy and safety of higher doses of metformin to determine its clinical potential. Second, many mitochondrial inhibitors are delivered into the mitochondria depending on the MMP. As such, imported drugs could inhibit ETC complexes and diminish the MMP, leading to decreased total agent importation [310, 311]. In addition, targeting the ETC is likely to be fraught with severe side effects. Some ETC inhibitors are considered neurotoxic, such as rotenone [312, 313], and some, such as cyanide, are even lethally toxic [314, 315]. In particular, IACS-010759, a CI inhibitor being advanced to clinical trials (NCT03291938 and NCT02882321; Table 2) [238, 316], has been associated with neuropathy and visual changes [49]. Moreover, metabolic plasticity promotes cancer cells to shift their metabolic features upon targeting specific metabolic vulnerabilities [317]. Furthermore, the selection of metabolic targets for therapeutic intervention has often been done in cell culture systems, where the metabolism of initial tumor-derived cells may be significantly affected by culture conditions [318]. These systems also do not recapitulate tumor heterogeneity and complex inter-tumor and tumor–host interactions [47].

Strategies for overcoming mitochondria-targeting bottlenecks to combat drug resistance

As mentioned above, limitations in drug sources and drug targeting challenge the application of targeting mitochondria for improving therapeutic efficiency in cancer treatment. Therefore, researchers are seeking new strategies to achieve a competitive advantage in targeting mitochondria for cancer therapy. Redevelopment and reuse of old drugs (repurposing/repositioning) represent such an opportunity to replenish the inventory of mitochondrial-targeted antitumor drugs [224]. Besides, the use of targeted nanomedicines offers innovative therapeutic strategies to overcome multiple barriers and selectively transport drug molecules to the mitochondria [319, 320]. Additionally, mitochondrial transplantation is an emerging approach that exerts antitumor potential by restoring mitochondrial function [321].

Drug repurposing for overcoming mitochondria-targeting bottlenecks

Drug repositioning is a strategy to identify medications that were initially used for the treatment of other noncancer illnesses for tumor therapy, based on an accumulated understanding of their mechanisms of action [322,319,324]. The advantages of this approach include, but are not limited to, the already established pharmacokinetic, pharmacodynamic, and toxicity profiles, their rapid progress into clinical trials, the significantly lower associated development cost as well as a relatively less risky business plan [325,322,327]. In recent years, technological innovation combined with the development of big data repositories and the analytical methods, as well as the emergence of a variety of innovative computational methods and in silico approaches, have greatly promoted the process of drug repurposing [328,325,326,331]. In this section, we present various promising repurposed non-oncology drugs that disrupt specific mitochondrial components and their functions for preclinical or clinical management of cancer drug resistance (Table 3).

Table 3 List of repurposed mitochondria-targeted drugs

Repositioning antidiabetic drugs

Metformin, an approved antidiabetic drug which has been used in cancer therapy, is one of the most successful repurposed drugs [332,329,330,335]. Several signaling pathways, including insulin/IGF1, NF-κB, AMPK/mTOR/PI3K, Ras/Raf/Erk, Wnt, Notch, and TGF-β signaling, have been identified to be involved in its antitumor effect [336,333,334,335,336,337,338,339,344]. Besides, metformin has been well demonstrated to target mitochondria and induce cytotoxic effects [345,342,343,348]. Numerous preclinical studies and clinical trials are investigating the therapeutic potential of metformin in many types of tumors [349,346,351]. Consistent with this, metformin was proven to enhance the anticancer effect of radio- or chemotherapies. For instance, Lee et al. observed that metformin could overcome resistance to cisplatin by downregulating RAD51 expression, representing a novel strategy in TNBC management [255]. In addition, in NSCLC, metformin acts synergistically with sorafenib to inhibit cell proliferation by activating AMPK, which holds significant potential to be tested in prospective clinical trials [352].

Other biguanides also exhibit enhanced antiproliferative or radio-sensitizing effects in cancer cells. For instance, HL156A, a metformin analog, markedly decreased MMP and induced ROS levels to activate caspase-3- and caspase-9-mediated apoptosis, thus suppressing tumor growth [353]. This study suggests the potential value of HL156A as a candidate for the treatment of oral cancer. Phenformin, a potent mitochondrial ETC inhibitor, also displayed remarkable anticancer activity against several tumors [354]. In colorectal cancer, phenformin could overcome hypoxic radio resistance through inhibition of mitochondrial respiration [355]. In breast cancer, phenformin synergistically decreased respiration and ATP production with oxamate, an inhibitor of lactate dehydrogenase, to inhibit tumor growth [356]. Furthermore, phenformin and oxamate displayed synergistic anticancer effects through simultaneously inhibiting mitochondrial complex I and cytosol LDH in this study.

Moreover, several other antidiabetic drugs have also been successively repurposed for cancer therapy and drug resistance management. Exendin-4 (Exe-4), a GLP-1 receptor agonist, was reported to elevate mitochondrial ROS and trigger subsequent apoptosis, which attenuated hyperglycemia-induced chemoresistance and sensitized human endometrial cancer cells to cisplatin treatment [357]. Canagliflozin, another antidiabetic drug, was identified to inhibit the proliferation of lung and prostate cancer cells, alone or in combination with ionizing radiation or chemotherapy using docetaxel by inhibiting mitochondrial CI supported respiration [358]. In addition, piperazine also targeted mitochondria to inhibit oxygen consumption, thus exhibiting an additive effect on inhibiting cell proliferation in combination with the glycolysis inhibitor 2-deoxyglucose (2-DG) [359].

Overall, repurposing antidiabetic drugs provides a plethora of candidates to suppress the growth of many types of tumors by targeting mitochondria. These drugs could not only increase the efficacy of standard therapies, but also reduce their side effects by potentially modulating metabolic plasticity.

Repositioning antimicrobial agents

Antimicrobial therapeutics, including antibiotics, anthelminthic and antifungal drugs, have been repurposed against tumors (e.g., breast, liver, colorectal and lung cancers, glioblastoma, multiple myeloma, and leukemia). A particularly important mechanism underlying their anticancer effects is interfering with mitochondrial function [360]. Examples of antibiotics that suppress cancer by altering mitochondria include the chloramphenicol family and tetracycline [361]. For instance, tigecycline preferentially inhibits the translation of mtDNA-encoded proteins to restrain the mitochondrial respiratory chain, causing mitochondrial dysfunction and increased oxidative stress, thus providing a therapeutic strategy for overcoming chemoresistance in human renal cell carcinoma and ovarian cancer [362, 363]. The antibiotic drug levofloxacin has also been repurposed to inhibit proliferation and trigger apoptosis of lung cancer cells by inducing mitochondrial dysfunction and oxidative damage [364].

In addition, several anthelminthic compounds were observed to interfere with mitochondria and combat with tumors. For instance, niclosamide could induce mitochondrial dysfunction and activate Bax and caspase-3, which attenuates migratory and invasive behaviors and promote apoptosis in thyroid cancer and chondrosarcoma tumors [365, 366]. Another anthelmintic drug, ivermectin, was suggested to inhibit angiogenesis, growth, and survival by decreasing mitochondrial respiration, membrane potential, and ATP levels [367]. The well-documented antimalarial agent artemisinin and its derivatives also possess potent anticancer activity through mitochondria-related pathways, manifesting as significantly reduced MMP, increased intracellular ROS and Ca2+ levels, and upregulated apoptosis-associated proteins [368, 369]. In particular, artesunate was reported to induce PINK1-dependent mitophagy to alter the cellular redox status in HeLa cells [370]. In addition, atovaquone, another antimalarial agent, can inhibit mitochondrial complex III, thereby increasing the efficacy of radiotherapy [371].

Antifungal agents also play an important role in drug repositioning strategies for the treatment of various tumors [372,369,374]. Itraconazole is among the most well-studied broad spectrum antifungal agents for cancer treatment [374,371,372,373,378]. It has been reported that itraconazole can interact with mitochondrial protein VDAC1 and modulate the AMPK/mTOR signaling axis [379, 380]. Another study has demonstrated that itraconazole elicited apoptosis by altering MMP, reducing Bcl-2 expression and elevating caspase-3 activity [381]. Our group previously found that ketoconazole, a P450 inhibitor traditionally used for antifungal treatment [382], elicited PINK1/Parkin-mediated mitophagy and apoptosis, thereby suppressing HCC growth alone or synergistically with sorafenib [383]. In addition, Econazole (Eco), a potent agent used for tackling superficial mycosis, is now well recognized as an antagonist for store-operated Ca2+ channels to induce cell death of leukemia [384,381,386]. Expectedly, it has now been shown to trigger mitochondrial-mediated apoptosis and cause cytochrome c leakage and apoptosis-inducing factor (AIF) translocation [387].

In conclusion, repurposing of broadly antimicrobial compounds emerges as an important strategy to provide complementary and alternative first-line drugs for effectively targeting mitochondria in cancer cells. We believe that repositioning antimicrobial agents will be an important topic in realizing the reversion of cancer drug resistance by eliciting mitochondria-dependent apoptosis.

Repositioning anti-cardiovascular disease drugs

Anti-cardiovascular disease drugs are another class of compounds that have attracted interest for their anticancer efficacy. An example is prazosin, an orally active postsynaptic selective alpha 1-adrenoreceptor antagonist used in treating hypertension, congestive heart failure (CHF), and even posttraumatic stress disorder (PTSD). It has been recognized to possess anticancer activity in some types of cancer by modulating the PI3K/Akt/mTOR signaling pathway [388]. Further, prazosin was demonstrated to intensify docetaxel-induced toxicity in prostate cancer cells [389]. In addition, another study demonstrated that prazosin triggers mitochondria-mediated caspase executing apoptotic pathways in PC-3 cells, thus significantly reducing tumor mass in PC-3-derived cancer xenografts [390]. Quercetin, a bioflavonoid with multiple activities including antihypertensive, and anti-inflammatory, has been repurposed for cancer treatment [391,388,393]. Accumulating studies have been devoted to exploring the molecular basis underlying the antitumor efficacy of quercetin. The decrease in MMP and subsequent apoptosis represent potential mechanisms [394,391,396]. Another antihypertensive drug, lercanidipine, was shown to induce apoptosis accompanied by severe vacuolation derived from the ER and mitochondria, thereby enhancing the cytotoxicity of various proteasome inhibitors, including bortezomib, carfilzomib, and ixazomib, in many solid tumor cells [397]. Furthermore, a widely used and safe antihypertensive drug, telmisartan, was suggested to alter cell bioenergetics by triggering mitochondrial fission and ROS accumulation, thereby sensitizing melanoma cells to treatment with vemurafenib [398].

Taken together, anti-cardiovascular disease drugs hold great potential to be endowed with novel characteristics to tackle tumors in a mitochondria-dependent way.

Repositioning antidepressant drugs and anti-neurodegenerative drugs

It has been increasingly recognized that antidepressant drugs exert anti-neoplastic properties, in addition to their well-documented ability to modulate neurotransmission [399,396,397,402]. Tricyclic antidepressants and their analogs are among the most well-studied repurposed drugs for cancer therapy. They have exhibited excellent efficacy in halting cancer cell growth and metastasis [403,400,401,406]. Interestingly, the antitumor efficacy of imipramine and amitriptyline primarily relies on their metabolic modulating ability in restoring the proper function of mitochondria, which differs from those functioning through disturbing mitochondria [407]. For instance, recent investigations showed that imipramine and amitriptyline restore stressed mitochondria and stimulate their function to hijack the aggressive character of cancer caused by mitochondrial dysfunction [408]. Chlorimipramine, another tricyclic antidepressant, has been shown to specifically inhibit mitochondrial CIII and cause decreased MMP as well as mitochondrial swelling and vacuolation, thus exhibiting a selective antitumor effect [409]. In addition, fluoxetine has been reported to increase doxorubicin accumulation within multiple drug-resistant (MDR) cells and inhibit drug efflux both in vivo and in vitro in resistant tumor models [410]. It is also able to induce mitochondria-mediated cell death in human epithelial ovarian cancer [411, 412]. Moreover, nortriptyline can induce both Fas, FasL, FADD axis-mediated extrinsic apoptosis and mitochondria dysfunction-triggered intrinsic apoptosis, thus suppressing bladder tumor growth in vivo [413].

Agents for treating neurodegenerative disease (such as Alzheimer’s and Epilepsy) have also been observed to be efficacious in the prevention and treatment of tumors [414, 415]. Valproic acid (VPA), an antiepileptic drug, has been shown to inhibit class I HDAC and exert antiproliferative, pro-apoptotic, and chemo-sensitizing effects in human lung cancer and colorectal cancer by restraining the cell cycle and eliciting ROS generation [416, 417]. In addition, VPA significantly induced mitochondrial dysfunction, thus reducing respiration and ATP production causing mitochondria-dependent apoptosis, which potentiated TRAIL-mediated cytotoxicity on cultured thoracic cancer and HCC cells [418, 419].

Repositioning anti-inflammatory and antirheumatic drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., indomethacin, ibuprofen, aspirin, and diclofenac) are the most commonly prescribed compounds for treating pain and inflammation [420,417,422]. It is widely accepted that NSAIDs possess anti-neoplastic effects in a wide spectrum of cancers [423,420,421,426]. In fact, prolonged NSAID administration reduces the risk of developing tumors [427, 428], and these non-oncology drugs are now applied to combination therapeutic regimens to potentiate the efficacy of chemotherapy and radiotherapy [429]. Based on the inhibitory effect on prostaglandin-synthesizing cyclooxygenases 1 and 2 (COX-1/2) and the role of nonsteroidal anti-inflammatory drug-induced gene NAG-1 in initiating the intrinsic apoptosis pathway [430], the mechanism of action underlying their antitumor efficacy is strongly related to mitochondrial dysfunction and ROS production caused by inhibition of mitochondrial respiration [431, 432]. This is best exemplified by aspirin, an FDA-approved NSAID for the treatment of pain and fever [433, 434]. Studies focusing on its antitumor mechanisms revealed that aspirin causes cytochrome c leakage and induces caspase-dependent apoptosis in cancer cells [435]. This mitochondrial damage is also probably responsible for the circumvention of resistance and sensitization to cisplatin by asplatin, a Pt(iv) prodrug of cisplatin, due to the ligation of aspirin [436]. Indomethacin, another NSAID initially used for treating rheumatic disease, has been found to induce mitochondria-mediated apoptosis in doxorubicin-resistant lung cancer cells through an MRP1-dependent mechanism [437]. In addition, indomethacin can activate the PKCζ-p38-DRP1 pathway to impair mitochondrial dynamics, thus inducing apoptosis in gastric cancer [438].

Other groups of anti-inflammatory and/or antirheumatic drugs also exhibit antitumor efficacy. Auranofin, an inhibitor of thioredoxin reductase (TrxR) initially developed for the treatment of rheumatoid arthritis, exhibited anticancer activity against various tumor types. It was approved for clinical trials in lung and ovarian carcinomas [439,436,437,438,443]. Further investigations revealed that auranofin targets both the cytosolic and mitochondrial forms of TrxR, indicating that mitochondrial alterations might participate in the inhibitory effect of auranofin on cancer [444, 445]. In addition, Euphorbia formosana Hayata (EF), a Taiwanese medicinal plant for the treatment of rheumatism, has been repurposed for tumor suppression by eliciting apoptosis via the Fas and mitochondrial pathways in leukemic cells [446].

In summary, anti-inflammatory agents, pain-relieving medication, and antirheumatic drugs are now documented to be effective again diverse critical disorders including cancer, for which mitochondrial-related mechanisms are well recognized to be involved in their antitumor effects.

Repositioning ion chelating agents

Ion chelating agents represent a category of effective antitumor agents by targeting mitochondria, as mitochondria use metals (such as iron, copper, calcium, zinc) for the synthesis of cofactors of oxidation–reduction enzymes [447]. Deferiprone (DFP), an iron chelator used clinically in thalassemia, kidney disease, and Friedreich’s ataxia, has been identified to reduce the proliferation and migration of cancer cells [448, 449]. The underlying mechanisms are well documented to involve the suppression of mitochondrial metabolism and the respiration rate, as well as induction of ROS production [450, 451]. VLX600, a recently designed iron chelator, has been characterized as a mitochondrial OXPHOS inhibitor which exhibited outstanding antitumor ability ovarian and breast and colorectal cancers [452,449,454]. Intriguingly, VLX600 was reported to inhibit mitochondrial respiration and augment the efficacy of imatinib in gastrointestinal stromal tumors [455]. It has also been suggested to sensitize ovarian cancer cells to platinum agents and PARPis (two standard-of-care therapies) [456].

Another metal with important functions in cancer progression is copper. Tetrathiomolybdate, a copper-chelating drug used in the treatment of copper overload disorder, has also shown obvious antitumor effects. Besides reducing angiogenesis, it can impair mitochondrial respiration as well as ATP production mainly by inhibiting copper-dependent mitochondrial C IV activity [457, 458]. In recent decades, disulfiram, the alcohol-aversion drug which functions in a copper complex to treat alcohol abuse [459], has attracted considerable attention for its alone or synergetic anticancer activity [460,457,458,459,460,465]. It functions as a disulfiram-Cu2+ complex (DSF-Cu+/Cu2+) to induce mitochondrial fission and reduce MMP, thus suppressing tumors via a redox-related apoptosis process [466]. In addition, elesclomol exerts potent anticancer activity by inducing oxidative stress and apoptosis [467,464,465,466,471]. Mechanistically, elesclomol forms an elesclomol-Cu (II) complex by chelating copper (Cu) outside of cells, which rapidly transports copper into the mitochondria, thus inducing mitochondrial ROS accumulation [472, 473]. Other types of metal chelators, including zinc and calcium chelating agents, have also been recognized as effective antitumor agents [474, 475].

Additionally, there are other compounds that do not belong to the groups discussed above which could be repositioned for cancer therapy via mitochondrial-mediated mechanisms. For instance, besides the palliative effects, cannabinoids and their analogs have shown promise as antitumor agents to reduce proliferation, induce apoptosis and autophagy, inhibit invasion and angiogenesis, and improve chemosensitivity to anticancer drugs [476]. Unequivocally, cannabinoids have been demonstrated to disrupt mitochondria damage and trigger ROS production both in human primary tumors and those resistant to chemotherapeutic drugs [477,474,479]. Furthermore, many commonly used chemotherapeutic drugs have been proven to interfere with mitochondria to promote anticancer effects, including, but not limited to, cisplatin [480, 481], doxorubicin [482, 483], sorafenib [484], and tamoxifen [485]. This broad variety of agents provide a plethora of options for tumor therapy by targeting mitochondria. We believe that targeted delivery of these drugs to mitochondria could benefit cancer treatment and overcome drug resistance.

In summary, repurposing non-oncology drugs is considered as an effective strategy to alleviate the current lack of mitochondria-targeting drugs. It holds the potential to develop effective agents in a short time period with lower development costs. However, it is not trivial to successfully apply suitable non-oncology drugs as anticancer therapeutics. Assessment of their effectiveness and understanding the underlying mechanistic in preclinical models are critical.

Mitochondria-targeted drug delivery system and multifunctional strategy

In recent years, organelle-specific delivery of bioactive molecules has been widely utilized for cancer treatment to achieve high selectivity, maximum therapeutic effects, minimum side effects, and minor resistance [486,483,484,485,490]. Mitochondria-targeting therapeutic strategies can directly affect the mitochondrial membrane or matrix, mitochondrial metabolism, and the mitochondrial apoptosis or regulatory signaling pathways [306, 491,488,489,494]. Researchers have developed or identified a number of mitochondria-targeted drug delivery systems (MTDDSs), with most of them currently transporting chemotherapeutics into the mitochondria based on the high membrane potential across the inner mitochondrial membrane or the mitochondrial protein import machinery [495,492,493,498]. The following section will provide insights into the application of novel mitochondria-targeting strategies for cancer therapy (Table 4).

Table 4 Representative mitochondria-targeting therapeutic regimens

Mitochondrial protein import machinery-based targeting strategies

Except for a small number of mitochondria-encoded factors (e.g., key proteins in the ETC, rRNAs, tRNAs), the vast majority of proteins present in the mitochondria are encoded by the nucleus and translocated from the cytosol [499,496,497,498,503]. Transporting machinery protein complexes (e.g., TIM/TOM complex) recognize and transport these proteins from the cytoplasm to the mitochondria, where proteins with mitochondria-targeting signal peptides (MTSs) are escorted from the cytosol to mitochondrial outer membrane [504, 505]. MTSs always exhibit positive charge and easily form amphiphilic α-helices and thus have been successfully used for the selective and effective delivery of therapeutics to mitochondria for disease treatment, including cancer therapy [506]. In addition, MTSs conjugate to, and deliver, a variety of cargo molecules (e.g., proteins, nucleic acids). For instance, p53-BakMTS/p53-Bax were synthesized via fusing p53 or its DNA-binding domain (DBD) to MTSs from Bak or Bax by Matissek et al. This regiment is capable of targeting p53 to the mitochondria and executing mitochondria-mediated apoptosis in cancers [507]. Several mitochondria-targeting units take advantage of the IMM-embedded transporters. For example, a self-assembled protein nanoparticle named GST-MT-3(Co2+) NPs was prepared by Zhu et al., via covalently conjugating paclitaxel to GST-MT-3(Co2+), to specifically target mitochondria. Co2+ in the NPs depolarized the MMP and elevated ROS, which subsequently induced apoptosis to execute antitumor effects. Intriguingly, this nanoparticle exhibited a synergistic effect manifesting as 50-fold lower paclitaxel dosage which possessed a highly effective antitumor effect [508]. Similarly, a functional hybrid peptide (MTS-R8H3) was used to prepare a modified targeted liposome, DOX/CEL-MTS-R8H3 lipo, for codelivery of doxorubicin hydrochloride (DOX) and celecoxib (CEL) [509]. This liposome codelivery system exhibited remarkable treatment efficacy on killing DOX-resistant MCF-7 (MCF-7/ADR) cells, providing a promising strategy for overcoming drug resistance in breast cancer.

Cell-penetrating peptide-based mitochondria-targeting strategies

Cell-penetrating peptides (CPPs) are nontoxic, short, cationic, and/or amphipathic peptides able to directly cross the cellular membrane [510,507,512]. They serve as a popular and efficient vector for delivering a broad variety of cargoes, including oligonucleotides, proteins, and therapeutics [513,510,515]. Many efforts are being made to improve their cell specificity for selective uptake by tumor cells, permitting medical applications [516,513,518]. Modifying the CPPs according to microenvironment condition is a widely used strategy. Particularly, mitochondria-penetrating peptides (MPPs) have been developed to deliver a variety of antitumor cargoes into mitochondria, which can inhibit tumor growth in vivo and in vitro [519,516,517,522]. For example, Dox was intercalated into the Cyt c aptamer contained DNA duplex and subsequently loaded in the dendrigraftpoly-L-lysines (DGL) and combine to cyclopeptide RA-V contained pH-sensitive liposomal shells, for preparing a MPP-modified DGLipo NPs. This system could successively deliver both DOX and RA-V into lysosome and mitochondria of cancer cells, and achieved a spatiotemporally controlled release of them to monitor cytochrome c release and apoptotic process, leading to enhanced therapeutic outcomes in MDR tumors [462]. In addition, the TAT-PEG-DOPE system (methoxy (polyethylene glycol)-2000–1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (mPEG-DOPE) and transactivator of transcription (TAT) peptide conjugated PEG-DOPE) is an example, in which sulfonamide will lose charge and detach when it suffers a decrease in pH, so that exposed TAT can interact and take the drug-loaded micelles to selectively kill tumor cells [523]. Several other novel CPPs for targeting cancer cell mitochondria, including Pal-pHK-pKV, an engineered peptide performed with the N-terminus of the HK-II protein [524]; pHK-PAS, achieved by covalently coupling N-terminal 15 aa of HKII (pHK) to a short, penetration-accelerating sequence (PAS) [525]; MTP3, another engineered peptide synthesized via resin-based solid-phase peptide synthesis, are also serving as efficient tools to deliver exogenous therapeutics into mitochondria and representing promising strategy in cancer therapy.

Delocalized lipophilic cation (DLC)-based mitochondria-targeting strategies

It has been well demonstrated that the MMPs of tumor cells are usually higher than that of non-malignant cells [526,523,528]. The hydrophobic surface areas and delocalized positive charge of DLCs permit them to rapidly pass through membrane bilayers and accumulate in cancer cells because of the more negative MMPs in cancer cells [529,526,527,532]. This offers a selective drug delivery approach to deliver compounds to tumors with little toxicity to normal healthy cells.

While Rhodamin123 was the first DLC identified to markedly inhibit the growth of carcinoma cell lines and prolong the survival of tumor-bearing mice [533, 534], the triphenylphosphonium (TPP) cation is the most well-documented DLC that has been used for mitochondria targeting [346, 495, 535]. TPP+ cations were conjugated to a wide variety of synthesized residues and incorporated into the liposomal lipid bilayer to make drug delivery systems for mitochondria targeting and tumor suppression [536,533,534,539]. For example, Biswas et al. synthesized a polyethylene glycol-phosphatidylethanolamine (PEG-PE) and TPP+ group modified liposomes (TPP-PEG-L). TPP-PEG-L has been demonstrated to enhance paclitaxel-induced cytotoxicity and antitumor efficacy compared to plain liposomes (PL) from efficient mitochondria targeting [540]. In addition, a D-α-tocopheryl polyethylene glycol-1000 succinate-triphenylphosphine (TPGS1000-TPP) was incorporated onto the surface of paclitaxel liposomes to prepare TPGS1000-TPP conjugate. This regiment could selectively accumulate into the mitochondria and initiate caspase-9- and caspase-3-mediated apoptosis, thereby exhibiting significant anticancer efficacy in drug-resistant A549/cDDP xenograft and cells [541].

Dequalinium chloride (DQA) has been regarded as a new class of anti-carcinoma agents based on its selective localization and accumulation within the mitochondria of cancer cells [542,539,544]. For example, a dequalinium polyethylene glycol-distearoylphosphatidyl-dylethanolamine (DQA-PEG2000-DSPE) conjugate was synthesized to develop mitochondrial-targeted resveratrol liposomes to overcome drug resistance. This mitochondrial-targeted liposome is significantly accumulated in the mitochondria and induces apoptosis in both nonresistant and resistant cancer cells by dissipating MMPs. In addition, cotreating this liposome with vinorelbine liposomes remarkably enhanced the anticancer efficacy against cisplatin-resistant A549 cells [545]. Furthermore, functional nanoparticles based on DQA were developed for targeted delivery of classical cytotoxic anticancer drugs (such as doxorubicin) to tumor cells, which showed significant anticancer efficacy in a drug-resistant tumor model via triggering cytochrome c release and mitochondrial apoptosis [546].

Newly developed mitochondria-targeting units-based strategies

In recent years, numerous drug delivery systems, including liposomes, micelles, “smart” polymers, and hydrogels, have been developed for cancer therapy [547,544,545,546,547,552]. For instance, to achieve accurate delivery to mitochondria with high specificity and low size, a native genetic system encoded in Salmonella pathogenicity island-1 (SPI-1) was used by Lim et al. [553]. In their study, E. coli carrying synthetic T3SS and MTD on plasmids could eliminate tumors and reduce the mortality of tumor-bearing animals. Furthermore, another study developed a peri-mitochondrial enzymatic self-assembly system to deliver chloramphenicol (CLRP) to the mitochondria in cancer cells. Importantly, their results suggested that this new system could overcome cisplatin resistance by inhibiting the synthesis of mitochondrial proteins.

Modifying traditional drugs with newly developed mitochondria-targeting units also exhibited potential to reduce side effects and reverse drug resistance to some extent [554, 555]. For instance, Ma et al. designed bromocoumarin platinum 1 therapeutic (a coumarin-Pt (IV) prodrug) to simultaneously target mitochondria and nuclei [556]. This therapy allows simultaneous accumulation of high concentrations of Pt in both the nDNA and mtDNA, thus triggering apoptosis to overcome cisplatin resistance. Moreover, p53 activation promoted Pt–DNA-induced apoptosis in cancer cells, leading to obvious anticancer activity with this prodrug. In addition, Xing and co-workers synthesized a mitochondria-targeting zeolitic imidazole framework loaded with platinum (ZIF-90@ DDP) to kill cancer cells by promoting effective drug release under specific pH and ATP levels, thus providing a new strategy for reversing platinum resistance in ovarian cancer [557].

Multifunctional drug delivery strategies

At present, mitochondria-targeting photothermal therapy (PTT), photodynamic therapy (PDT), chemo-dynamic therapy (CDT), and related combinational therapies have attracted global attention due to their advantages of a wide therapeutic range, minimal toxicity, excellent safety profile, noninvasiveness, and low drug resistance [558,555,560]. PTT triggers thermal damage by conversing light energy into heat to kill cancer cells [561,558,563]. In recent years, a variety of photothermal materials, including inorganic nanomaterials (such as gold nanocages, gold nanorods, and other gold nanostructures), transition metal sulfide or oxide nanoparticles, have been developed to improve the energy conversion from near infrared (NIR) light [564, 565]. As such, PTT has shown remarkable achievements in the treatment of various tumors [566,563,564,569]. PDT is available for treating a broad variety of cancers through local ROS production only in the light-exposed region by utilizing photosensitizer (PS), light, and oxygen [570,571,572,573]. Recently, Fe3O4@Dex-TPP nanoparticles have been prepared by coprecipitation in TPP-grafted dextran (Dex-TPP) and Fe2+/Fe3+ and then incorporated with the photosensitizers of protoporphyrin IX (PpIX) and glutathione-responsive mPEG-ss-COOH to form a fenton reaction-assisted PDT, noted Fe3O4@Dex/TPP/PpIX/ss-mPEG nanoparticles [574]. This nanoparticle targets mitochondria by photoinduced internalization, leading to ROS generation and the fenton reaction-produced O2, thus significantly improving the therapeutic efficacy on tumor. In addition, Zeng et al. synthesized bifunctional nanoprobe (FA-NPs-DOX) by loading DOX to NaYF4:Yb/Tm-TiO2 inorganic photosensitizers for in vivo inorganic PDT [575]. In this study, folic acid (FA) targeting and NIR-triggered inorganic PDT accelerated the release of DOX and promoted the inhibition rate in drug-sensitive MCF-7 and resistant MCF-7/ADR cells.

In addition, other therapies, including CDT [576, 577], sonodynamic therapy (SDT), gas therapy, radiation therapy (RDT), alone or in combination with other treatments targeting mitochondria to inhibit tumors, are emerging, as described in a comprehensive review [491]. For instance, Shi et al. designed a mitochondria-targeted hollow mesoporous silica nanoparticles (THMSNs) loaded with L-menthol (LM) to carry DOX and NIR dye indocyanine green (ICG), named THMSNs@LMDI [578]. Under NIR irradiation, this system simultaneously produces photodynamic and photothermal therapy effect via DOX release and apoptosis activation, thereby sensitizing A549/MCF-7 cells to DOX. Intriguingly, a specific targeting of mitochondria and imaging-guided chemo-photothermal therapy against cisplatin resistance was proposed by Yang and colleagues [579]. In this work, Pt (IV)-NPs, a nanoparticle precisely assembled by biotin-labeled Pt (IV) prodrug derivative and cyclodextrin-functionalized IR780, integrated with targeting units, imaging moieties into a single regiment to overcome and even completely eliminate cisplatin resistance A549R tumors, thus providing a beneficial precise therapeutic. Undoubtedly, combination therapies achieve synergistic effect of anticancer and hold more beneficial for future clinical translation.

In summary, the development of mitochondria-targeting units and combinational strategies for cancer therapy has achieved precise treatment at lower drug doses (Table 4), offering excellent prospects for improving the therapeutic effect and overcoming drug resistance.

Therapeutic applications of mitochondrial transplantation

The transplantation of mitochondria from healthy cells to abnormal cells has emerged as a novel and attractive therapeutic strategy to treat diseases caused by mitochondria damage or dysfunction [591,587,588,589,595]. While intercellular mitochondrial transfer functions as essential stress-adaptive mechanism to endow cancer cells with resistance to chemotherapy [175, 176], mitochondrial transplantation (mtTP) has been used in preclinical and clinical studies to restore mitochondrial function for cancer therapy and eliminate drug resistance [596,592,593,599]. For example, Chang et al. transferred mitochondria into breast cancer cell lines [321]. The results suggested that mitochondria transplantation-induced cell apoptosis inhibited cell growth and decreased oxidative stress, thereby increasing the susceptibility of both MCF-7 and MDA-MB-231 breast cancer cells to doxorubicin and paclitaxel. In addition, intercellular endocytosis (e.g., mitochondria internalization) was suggested to enhance the TCA cycle and aerobic respiration, attenuate glycolysis, and reactivate the mitochondrial apoptotic pathway, thereby inhibiting malignant proliferation and enhancing the radiosensitivity of gliomas in vitro and in vivo [600].

Overall, mtTP appears to be a very promising therapeutic option to fine-tune mitochondria function in cancer cells so that drug resistance might be overcome. However, research on mitochondrial transplantation for cancer treatment is still in its infancy. Further investigations including preclinical and clinical studies are required to determine if it is effective in sensitizing cancer cells to radio- or chemotherapy. Additionally, various technical and ethical issues need to be addressed before its actual clinical application.

Conclusions and perspectives

Mitochondria are crucial players in cancer cell survival, as they are the bioenergetic and biosynthetic hub that coordinates cellular respiration, FAO, the TCA cycle, ETC, Ca2+ signaling, and redox homeostasis. Cancer drug resistance, as an adaptive strategy employed by cancer cells to survive stress conditions, is inevitably associated with mitochondrial-related pathways [62, 82, 601]. In fact, emerging evidence strongly indicates that resistant tumor cells exhibit high mitochondrial respiration and OXPHOS status [602, 603]. Therefore, targeting mitochondria represents a promising cancer treatment avenue and chemoresistance overcoming strategy. In this review, we have elaborated on the mechanisms of mitochondrial dynamics in number, structure, and location to maintaining mitochondrial function to endow cancer cells with metabolic flexibility for adapting to stress conditions, with an emphasis on their regulatory role in drug resistance. We have also summarized recent advances that focus on developing therapeutics that specifically target the mitochondria for cancer therapy. Notably, two representative compounds, metformin and CPI-613, have been taken on to phase III clinical trials (Table 2). Lastly, we have highlighted the repurposing of “old” drugs for mitochondria targeting in tumor therapy with the potential to effectively kill tumors. The development of mitochondria-targeting approaches will undisputedly boost the precision of cancer treatment at lower drug doses (Fig. 4, Table 5).

Fig. 4
figure 4

Schematic illustration of the mitochondria-targeting strategies and their anticancer effect. Integrated therapeutics include, but are not limited to, PTT, PDT, and CDT. Their function requires the rational design, functionalization, and application of diverse mitochondria-targeting units, such as organic phosphine/sulfur salts, QA salts, transition metal complexes, and MTPs. The generation of superoxide (·O2), singlet oxygen (1O2), ·OH or heat results in mitochondrial damage, thus inhibiting energy supply and triggering cancer cells death

Table 5 Overview of mitochondria-targeting strategies for cancer treatment

It is worth noting that further investigations are urgently needed to handle several key mitochondrial-related questions for their successful application in clinic cancer treatment. First, it will be pivotal to identify additional molecular mechanisms that cause the high OXPHOS status of cancer cells. It is also important to explore the roles and mechanisms of metabolic advantages in maintaining this high OXPHOS activity and how they modulate resistance to targeted or chemotherapies, as mitochondria are the hub of many metabolic pathways. Second, the roles of mitochondrial reshaping, rebuilding, and recycling are largely in a context-dependent manner, which remain vastly unexplored. Further study focusing on developing rational targeted approaches to modulate adaptive response will definitely require the possibility to accurately map dynamic processes and monitor bioenergetic and metabolic changes over a considerable time period [621]. Theoretically, drug repurposing and systematic screening approaches as well as advanced bioinformatics could replenish the inventory of antitumor drugs and break one of the current bottlenecks of drug development. However, it is important to decipher their mechanism of action and identify patients who would benefit from treatment with these compounds. In addition, more preclinical studies and clinical trials must be completed before such interventions become common practice in cancer therapy.

Modification of traditional therapeutics with mitochondria-targeting units has potential for reducing drug resistance and adverse side effects. Many of these strategies have been applied as preclinical or clinical antitumor therapies. However, safety evaluation based on biocompatibilities, release, accumulation, and metabolism is a prerequisite for their application. Indeed, limitations in the materials, such as toxicities and poor drug loadings, have restricted the further application of multifunctional nanodrugs. Future pharmaceutical research should focus on addressing the aspects mentioned above while exploring new materials. Notably, these therapeutics need to overcome both physiological and biological barriers before localizing to their target sites to take effect. What happens in these processes will affect the release of drugs and affect their antitumor efficacy. Therefore, it is important to endow the delivery system with some specific related functions. In addition to structural reformation, future research needs to investigate the mechanisms of exerting treatment, especially at the molecular level.

In the coming years, we predict that advances in omics technology, PET imaging combined with cancer genomics, will help a timely elucidation of metabolic vulnerabilities and lead to the recognition of rational combinations of mitochondria-targeting inhibitors with standard treatments, which will hopefully bring new and more effective strategies for cancer therapy and drug resistance management (Fig. 5) supporting precision/personalized medicine.

Fig. 5
figure 5

Rational design for targeting mitochondria in cancer therapy. Drug repurposing, mitochondrial-targeted nanomedicines, and mitochondrial transplantation represent opportunity to offer promising strategies for targeting mitochondria to overcome cancer drug resistance. The mitochondrial inhibitors may be used in combination with chemotherapy, radiotherapy, or even immunotherapy to provide new avenues for cancer therapeutic regimes

Availability of data and materials

Not applicable.









Alpha-tocopheryl succinate






Acute myeloid leukemia


α-Ketoglutarate dehydrogenase


Apoptosis-inducing factor


Antioxidant response elements


RAC-alpha serine/threonine-protein kinase


Bcl2/adenovirus E1B 19 kDa interacting protein 3


Bcl-2-like protein 13


Bone marrow stromal cells


1:4-Benzodiazepine derivative


Benzyl isothiocyanate


Cancer stem cells


Cell-penetrating peptides


Chemo-dynamic therapy


Carnitine palmitoyltransferase ½


Congestive heart failure


Cyclooxygenases 1 and 2




Dequalinium chloride




Dynein-related protein 1






Dihydroorotate dehydrogenase




Epidermal growth factor receptor


Extracellular vesicles


Electron transport chain


Endoplasmic reticulum


Esophageal squamous cell carcinoma


Euphorbia formosana Hayata


FUN14 domain-containing protein 1


Ferredoxin 1


Fission protein homologous protein 1


Fatty acid oxidation


Fatty acids


Glycine cleavage system


Glucose transporter 1




Glutamate dehydrogenase 1


Glutamate oxaloacetate transaminase 2


Glutamate pyruvate transaminase 2




Hexokinase 2


Hepatocellular carcinoma


Histone deacetylase


Inner mitochondrial membrane


Isocitrate dehydrogenase


Lactate dehydrogenase


Methylenetetrahydrofolate dehydrogenase 1


Methylenetetrahydrofolate dehydrogenase 1-like


Methylenetetrahydrofolate dehydrogenase 2


Multiple drug-resistant


Mitochondria-targeting peptides




Myeloid leukemia cell differentiation protein


Mitochondrial-associated endoplasmic reticulum membrane


Mitochondrial Ca2+ uniporter complex


Marrow stromal cells


Multiple myeloma


Mitochondrial-derived peptides


Monocarboxylate transporter


Mitochondria-targeted drug delivery systems


Mitochondria-targeting signal peptides


Mitochondria-penetrating peptides




Nonsteroidal anti-inflammatory drugs




Non-small cell lung cancer


Near infrared


Oxidative phosphorylation


Outer mitochondrial membrane


Optic atrophy 1




Polyethylene glycol-phosphatidylethanolamine


Pyruvate kinase isozymes M2


Pentose phosphate pathway


Peroxisome proliferator-activated receptorγcoactivator-1


Plain liposomes


Phosphatidylinositol 3-kinase


Photodynamic therapy


Photothermal therapy


Pyruvate dehydrogenase


Posttraumatic stress disorder


Pyruvate dehydrogenase


Radiation therapy


Reactive oxygen species


Receptor-interacting protein kinase 1


Serine hydroxymethyltransferase


Short open reading frames


Salmonella pathogenicity island-1


Sonodynamic therapy


Transcription factor A, mitochondrial


Tyrosine kinase inhibitors

TCA cycle:

Tricarboxylic acid cycle


Tunneling nanotubes


Triple-negative breast cancer




Transactivator of transcription


Thioredoxin reductase


Unfolded protein stress response


Voltage-dependent anion-selective channel 1


Valproic acid


Voltage-dependent anion-selective channel proteins


Vitamin K3


  1. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13:714–26.

    CAS  PubMed  Article  Google Scholar 

  2. Phan TG, Croucher PI. The dormant cancer cell life cycle. Nat Rev Cancer. 2020;20:398–411.

    CAS  PubMed  Article  Google Scholar 

  3. Hanker AB, Sudhan DR, Arteaga CL. Overcoming endocrine resistance in breast cancer. Cancer Cell. 2020;37:496–513.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27.

    CAS  PubMed  Article  Google Scholar 

  5. Marine J-C, Dawson S-J, Dawson MA. Non-genetic mechanisms of therapeutic resistance in cancer. Nat Rev Cancer. 2020;20:743–56.

    CAS  PubMed  Article  Google Scholar 

  6. Braun TP, Eide CA, Druker BJ. Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell. 2020;37:530–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Jiang J, Zhang L, Chen H, Lei Y, Zhang T, Wang Y, Jin P, Lan J, Zhou L, Huang Z, et al. Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma. Autophagy. 2020;16:106–22.

    CAS  PubMed  Article  Google Scholar 

  8. Zhang Z, Qin S, Chen Y, Zhou L, Yang M, Tang Y, Zuo J, Zhang J, Mizokami A, Nice EC, Chen HN, Huang C, Wei X. Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy. EMBO Mol Med. 2022;14(2):e14903.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Rohwer N, Cramer T. Hypoxia-mediated drug resistance: novel insights on the functional interaction of HIFs and cell death pathways. Drug Resistance Updates. 2011;14:191–201.

    CAS  PubMed  Article  Google Scholar 

  10. Boulos JC, Yousof Idres MR, Efferth T. Investigation of cancer drug resistance mechanisms by phosphoproteomics. Pharmacol Res. 2020;160:105091.

    CAS  PubMed  Article  Google Scholar 

  11. Li B, Jiang J, Assaraf YG, Xiao H, Chen Z-S, Huang C. Surmounting cancer drug resistance: new insights from the perspective of N-methyladenosine RNA modification. Drug Resistance updates. 2020;53:100720.

    PubMed  Article  Google Scholar 

  12. Jin P, Jiang J, Xie N, Zhou L, Huang Z, Zhang L, Qin S, Fu S, Peng L, Gao W, et al. MCT1 relieves osimertinib-induced CRC suppression by promoting autophagy through the LKB1/AMPK signaling. Cell Death Dis. 2019;10:615.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. Gong K, Guo G, Gerber DE, Gao B, Peyton M, Huang C, Minna JD, Hatanpaa KJ, Kernstine K, Cai L, et al. TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. J Clin Investig. 2018;128:2500–18.

    PubMed  PubMed Central  Article  Google Scholar 

  14. Eritja N, Chen B-J, Rodríguez-Barrueco R, Santacana M, Gatius S, Vidal A, Martí MD, Ponce J, Bergadà L, Yeramian A, et al. Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer. Autophagy. 2017;13:608–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Ghosh JC, Siegelin MD, Vaira V, Faversani A, Tavecchio M, Chae YC, Lisanti S, Rampini P, Giroda M, Caino MC, et al. Adaptive mitochondrial reprogramming and resistance to PI3K therapy. J Natl Cancer Inst. 2015;107.

  16. Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5:8.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. Payandeh Z, Pirpour Tazehkand A, Barati G, Pouremamali F, Kahroba H, Baradaran B, Samadi N. Role of Nrf2 and mitochondria in cancer stem cells; in carcinogenesis, tumor progression, and chemoresistance. Biochimie. 2020;179:32–45.

    CAS  PubMed  Article  Google Scholar 

  18. Qin S, Li B, Ming H, Nice EC, Zou B, Huang C. Harnessing redox signaling to overcome therapeutic-resistant cancer dormancy. Biochimica et Biophysica Acta (BBA) - Rev Cancer. 2022;1877(4):188749.

  19. Li B, Huang Y, Ming H, Nice EC, Xuan R, Huang C. Redox Control of the Dormant Cancer Cell Life Cycle. Cells. 2021;10(10):2707.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Smith RL, Soeters MR, Wüst RCI, Houtkooper RH. Metabolic flexibility as an adaptation to energy resources and requirements in health and disease. Endocr Rev. 2018;39:489–517.

    PubMed  PubMed Central  Article  Google Scholar 

  21. Boumahdi S, de Sauvage FJ. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat Rev Drug Discovery. 2020;19:39–56.

    CAS  PubMed  Article  Google Scholar 

  22. Cao Y. Adipocyte and lipid metabolism in cancer drug resistance. J Clin Investig. 2019;129:3006–17.

    PubMed  PubMed Central  Article  Google Scholar 

  23. Iwamoto H, Abe M, Yang Y, Cui D, Seki T, Nakamura M, Hosaka K, Lim S, Wu J, He X, et al. Cancer lipid metabolism confers antiangiogenic drug resistance. Cell Metabolism. 2018;28.

  24. Yoshida GJ. Metabolic reprogramming: the emerging concept and associated therapeutic strategies. J Exp Clin Cancer Res: CR. 2015;34:111.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. Liu R, Lee J-H, Li J, Yu R, Tan L, Xia Y, Zheng Y, Bian X-L, Lorenzi PL, Chen Q, et al. Choline kinase alpha 2 acts as a protein kinase to promote lipolysis of lipid droplets. Mol Cell. 2021;81.

  26. Liu R, Li J, Shao J, Lee J-H, Qiu X, Xiao Y, Zhang B, Hao Y, Li M, Chen Q. Innate immune response orchestrates phosphoribosyl pyrophosphate synthetases to support DNA repair. Cell Metab. 2021;33.

  27. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Kreuzaler P, Panina Y, Segal J, Yuneva M. Adapt and conquer: metabolic flexibility in cancer growth, invasion and evasion. Mol Metab. 2020;33.

  29. Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol. 2011;27:441–64.

    CAS  PubMed  Article  Google Scholar 

  30. Luengo A, Li Z, Gui DY, Sullivan LB, Zagorulya M, Do BT, Ferreira R, Naamati A, Ali A, Lewis CA, et al. Increased demand for NAD relative to ATP drives aerobic glycolysis. Mol Cell. 2021;81.

  31. Liu J, Zhang C, Hu W, Feng Z. Tumor suppressor p53 and metabolism. J Mol Cell Biol. 2019;11:284–92.

    CAS  PubMed  Article  Google Scholar 

  32. Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20:74–88.

    CAS  PubMed  Article  Google Scholar 

  33. Papagiannakopoulos T, Bauer MR, Davidson SM, Heimann M, Subbaraj L, Bhutkar A, Bartlebaugh J, Vander Heiden MG, Jacks T. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab. 2016;24:324–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell. 2017;66:789–800.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Lin S-C, Hardie DG. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 2018;27:299–313.

    CAS  PubMed  Article  Google Scholar 

  36. Labuschagne CF, Zani F, Vousden KH. Control of metabolism by p53: cancer and beyond. Biochim Biophys Acta. 2018;1870:32–42.

    CAS  PubMed Central  Google Scholar 

  37. Gomes AS, Ramos H, Soares J, Saraiva L. p53 and glucose metabolism: an orchestra to be directed in cancer therapy. Pharmacol Res. 2018;131:75–86.

    CAS  PubMed  Article  Google Scholar 

  38. Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17:351–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Zhang Y, Yu G, Chu H, Wang X, Xiong L, Cai G, Liu R, Gao H, Tao B, Li W, et al. Macrophage-associated PGK1 phosphorylation promotes aerobic glycolysis and tumorigenesis. Mol Cell. 2018;71.

  40. Park MK, Zhang L, Min K-W, Cho J-H, Yeh C-C, Moon H, Hormaechea-Agulla D, Mun H, Ko S, Lee JW, et al. NEAT1 is essential for metabolic changes that promote breast cancer growth and metastasis. Cell Metab. 2021;33.

  41. Lin J, Xia L, Liang J, Han Y, Wang H, Oyang L, Tan S, Tian Y, Rao S, Chen X, et al. The roles of glucose metabolic reprogramming in chemo- and radio-resistance. J Exp Clin Cancer Res. 2019;38:218.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. Botzer LE, Maman S, Sagi-Assif O, Meshel T, Nevo I, Yron I, Witz IP. Hexokinase 2 is a determinant of neuroblastoma metastasis. Br J Cancer. 2016;114:759–66.

    PubMed  Article  CAS  Google Scholar 

  43. Marcucci F, Rumio C. Glycolysis-induced drug resistance in tumors-A response to danger signals? Neoplasia. 2021;23:234–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Wong T-L, Ng K-Y, Tan KV, Chan L-H, Zhou L, Che N, Hoo RLC, Lee TK, Richard S, Lo C-M, et al. CRAF methylation by PRMT6 regulates aerobic glycolysis-driven hepatocarcinogenesis via ERK-dependent PKM2 nuclear relocalization and activation. Hepatology (Baltimore, MD). 2020;71:1279–96.

    CAS  Article  Google Scholar 

  45. Ma L, Zong X. Metabolic symbiosis in chemoresistance: refocusing the role of aerobic glycolysis. Front Oncol. 2020;10:5.

    PubMed  PubMed Central  Article  Google Scholar 

  46. Fendt S-M, Frezza C, Erez A. Targeting metabolic plasticity and flexibility dynamics for cancer therapy. Cancer Discov. 2020;10:1797–807.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Méndez-Lucas A, Lin W, Driscoll PC, Legrave N, Novellasdemunt L, Xie C, Charles M, Wilson Z, Jones NP, Rayport S, et al. Identifying strategies to target the metabolic flexibility of tumours. Nat Metab. 2020;2:335–50.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. Oshima N, Ishida R, Kishimoto S, Beebe K, Brender JR, Yamamoto K, Urban D, Rai G, Johnson MS, Benavides G, et al. Dynamic imaging of LDH inhibition in tumors reveals rapid in vivo metabolic rewiring and vulnerability to combination therapy. Cell Rep. 2020;30.

  49. Stine ZE, Schug ZT, Salvino JM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov. 2022;21:141–62.

    CAS  PubMed  Article  Google Scholar 

  50. Wang K, Jiang J, Lei Y, Zhou S, Wei Y, Huang C. Targeting metabolic-redox circuits for cancer therapy. Trends Biochem Sci. 2019;44:401–14.

    CAS  PubMed  Article  Google Scholar 

  51. Jourdain AA, Begg BE, Mick E, Shah H, Calvo SE, Skinner OS, Sharma R, Blue SM, Yeo GW, Burge CB, et al. Loss of LUC7L2 and U1 snRNP subunits shifts energy metabolism from glycolysis to OXPHOS. Mol Cell. 2021;81.

  52. Guitart AV, Panagopoulou TI, Villacreces A, Vukovic M, Sepulveda C, Allen L, Carter RN, van de Lagemaat LN, Morgan M, Giles P, et al. Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions. J Exp Med. 2017;214:719–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Stuani L, Sabatier M, Saland E, Cognet G, Poupin N, Bosc C, Castelli FA, Gales L, Turtoi E, Montersino C, et al. Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia. J Exp Med. 2021;218.

  54. Kim M, Gwak J, Hwang S, Yang S, Jeong SM. Mitochondrial GPT2 plays a pivotal role in metabolic adaptation to the perturbation of mitochondrial glutamine metabolism. Oncogene. 2019;38:4729–38.

    CAS  PubMed  Article  Google Scholar 

  55. Eisner V, Picard M, Hajnóczky G. Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol. 2018;20:755–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Missiroli S, Perrone M, Genovese I, Pinton P, Giorgi C. Cancer metabolism and mitochondria: finding novel mechanisms to fight tumours. EBioMedicine. 2020;59:102943.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Marchi S, Giorgi C, Galluzzi L, Pinton P. Ca Fluxes and Cancer. Mol Cell. 2020;78:1055–69.

    CAS  PubMed  Article  Google Scholar 

  58. Song K-H, Kim J-H, Lee Y-H, Bae HC, Lee H-J, Woo SR, Oh SJ, Lee K-M, Yee C, Kim BW, et al. Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance. J Clin Investig. 2018;128:4098–114.

    PubMed  PubMed Central  Article  Google Scholar 

  59. Guerra F, Arbini AA, Moro L. Mitochondria and cancer chemoresistance. Biochim Biophys Acta Bioenerg. 2017;1858:686–99.

    CAS  PubMed  Article  Google Scholar 

  60. Han Y, Kim B, Cho U, Park IS, Kim SI, Dhanasekaran DN, Tsang BK, Song YS. Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells. Oncogene. 2019;38:7089–105.

    CAS  PubMed  Article  Google Scholar 

  61. Xie L, Shi F, Li Y, Li W, Yu X, Zhao L, Zhou M, Hu J, Luo X, Tang M, et al. Drp1-dependent remodeling of mitochondrial morphology triggered by EBV-LMP1 increases cisplatin resistance. Signal Transduct Target Ther. 2020;5:56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Kuntz EM, Baquero P, Michie AM, Dunn K, Tardito S, Holyoake TL, Helgason GV, Gottlieb E. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat Med. 2017;23:1234–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Liu J, Zhu C, Xu L, Wang D, Liu W, Zhang K, Zhang Z, Shi J. Nanoenabled intracellular calcium bursting for safe and efficient reversal of drug resistance in tumor cells. Nano Lett. 2020;20:8102–11.

    CAS  PubMed  Article  Google Scholar 

  64. Yao J, Wang J, Xu Y, Guo Q, Sun Y, Liu J, Li S, Guo Y, Wei L. CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma. Autophagy. 2021.

  65. Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol. 2020;21:204–24.

    CAS  PubMed  Article  Google Scholar 

  66. Pernas L, Scorrano L. Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu Rev Physiol. 2016;78:505–31.

    CAS  PubMed  Article  Google Scholar 

  67. Chan DC. Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol. 2020;15:235–59.

    CAS  PubMed  Article  Google Scholar 

  68. Porporato PE, Filigheddu N, Pedro JMB, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res. 2018;28:265–80.

    CAS  PubMed  Article  Google Scholar 

  69. Burke PJ. Mitochondria, bioenergetics and apoptosis in cancer. Trends Cancer. 2017;3:857–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Garbincius JF, Elrod JW. Mitochondrial calcium exchange in physiology and disease. Physiol Rev. 2022;102:893–992.

    CAS  PubMed  Article  Google Scholar 

  71. Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ. Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med. 2019;51:1–13.

    CAS  PubMed  Article  Google Scholar 

  72. Willems PH, Rossignol R, Dieteren CE, Murphy MP, Koopman WJ. Redox homeostasis and mitochondrial dynamics. Cell Metab. 2015;22:207–18.

    CAS  PubMed  Article  Google Scholar 

  73. Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21:85–100.

    CAS  PubMed  Article  Google Scholar 

  74. Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer. 2014;14:709–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Stacpoole PW. Therapeutic targeting of the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer. J Natl Cancer Inst. 2017;109.

  76. Morris JPt, Yashinskie JJ, Koche R, Chandwani R, Tian S, Chen CC, Baslan T, Marinkovic ZS, Sanchez-Rivera FJ, Leach SD, et al. alpha-Ketoglutarate links p53 to cell fate during tumour suppression. Nature. 2019;573:595–9.

  77. Wang YP, Sharda A, Xu SN, van Gastel N, Man CH, Choi U, Leong WZ, Li X, Scadden DT. Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis. Cell Metab. 2021;33(1027–41): e8.

    Google Scholar 

  78. Dalla Pozza E, Dando I, Pacchiana R, Liboi E, Scupoli MT, Donadelli M, Palmieri M. Regulation of succinate dehydrogenase and role of succinate in cancer. Semin Cell Dev Biol. 2020;98:4–14.

    CAS  PubMed  Article  Google Scholar 

  79. Izzo V, Bravo-San Pedro JM, Sica V, Kroemer G, Galluzzi L. Mitochondrial permeability transition: new findings and persisting uncertainties. Trends Cell Biol. 2016;26:655–67.

    CAS  PubMed  Article  Google Scholar 

  80. McGranahan N, Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell. 2017;168:613–28.

    CAS  PubMed  Article  Google Scholar 

  81. Ciplea AG, Richter KD. The protective effect of Allium sativum and crataegus on isoprenaline-induced tissue necroses in rats. Arzneimittelforschung. 1988;38:1583–92.

    CAS  PubMed  Google Scholar 

  82. Lee K-M, Giltnane JM, Balko JM, Schwarz LJ, Guerrero-Zotano AL, Hutchinson KE, Nixon MJ, Estrada MV, Sánchez V, Sanders ME, et al. MYC and MCL1 cooperatively promote chemotherapy-resistant breast cancer stem cells via regulation of mitochondrial oxidative phosphorylation. Cell Metab. 2017;26.

  83. Wai T, Langer T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab. 2016;27:105–17.

    CAS  PubMed  Article  Google Scholar 

  84. Desai R, East DA, Hardy L, Faccenda D, Rigon M, Crosby J, Alvarez MS, Singh A, Mainenti M, Hussey LK, et al. Mitochondria form contact sites with the nucleus to couple prosurvival retrograde response. Sci Adv. 2020;6.

  85. Drabik K, Malińska D, Piecyk K, Dębska-Vielhaber G, Vielhaber S, Duszyński J, Szczepanowska J. Effect of chronic stress present in fibroblasts derived from patients with a sporadic form of AD on mitochondrial function and mitochondrial turnover. Antioxidants (Basel, Switzerland). 2021;10.

  86. LeBleu VS, O'Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 2014;16.

  87. Dang CV, Le A, Gao P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res. 2009;15:6479–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA, Kim J-W, Yustein JT, Lee LA, Dang CV. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol. 2005;25:6225–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Yun CW, Han Y-S, Lee SH. PGC-1α Controls mitochondrial biogenesis in drug-resistant colorectal cancer cells by regulating endoplasmic reticulum stress. Int J Mol Sci. 2019;20.

  90. Jiang J, Wang K, Chen Y, Chen H, Nice EC, Huang C. Redox regulation in tumor cell epithelial-mesenchymal transition: molecular basis and therapeutic strategy. Signal Transduct Target Ther. 2017;2:17036.

    PubMed  PubMed Central  Article  Google Scholar 

  91. Zhang G, Frederick DT, Wu L, Wei Z, Krepler C, Srinivasan S, Chae YC, Xu X, Choi H, Dimwamwa E, et al. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. J Clin Invest. 2016;126:1834–56.

    PubMed  PubMed Central  Article  Google Scholar 

  92. Xu R, Luo X, Ye X, Li H, Liu H, Du Q, Zhai Q. SIRT1/PGC-1α/PPAR-γ correlate with hypoxia-induced chemoresistance in non-small cell lung cancer. Front Oncol. 2021;11:682762.

    PubMed  PubMed Central  Article  Google Scholar 

  93. Gopal YNV, Rizos H, Chen G, Deng W, Frederick DT, Cooper ZA, Scolyer RA, Pupo G, Komurov K, Sehgal V, et al. Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. Can Res. 2014;74:7037–47.

    CAS  Article  Google Scholar 

  94. McCann E, O’Sullivan J, Marcone S. Targeting cancer-cell mitochondria and metabolism to improve radiotherapy response. Translational oncology. 2021;14:100905.

    PubMed  Article  CAS  Google Scholar 

  95. Kondapalli C, Kazlauskaite A, Zhang N, Woodroof HI, Campbell DG, Gourlay R, Burchell L, Walden H, Macartney TJ, Deak M, et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biol. 2012;2: 120080.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. O’Flanagan CH, Morais VA, Wurst W, De Strooper B, O’Neill C. The Parkinson’s gene PINK1 regulates cell cycle progression and promotes cancer-associated phenotypes. Oncogene. 2015;34:1363–74.

    CAS  PubMed  Article  Google Scholar 

  97. Wu H, Wang Y, Li W, Chen H, Du L, Liu D, Wang X, Xu T, Liu L, Chen Q. Deficiency of mitophagy receptor FUNDC1 impairs mitochondrial quality and aggravates dietary-induced obesity and metabolic syndrome. Autophagy. 2019;15:1882–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Yan C, Gong L, Chen L, Xu M, Abou-Hamdan H, Tang M, Désaubry L, Song Z. PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy. 2020;16:419–34.

    CAS  PubMed  Article  Google Scholar 

  99. Murakawa T, Yamaguchi O, Hashimoto A, Hikoso S, Takeda T, Oka T, Yasui H, Ueda H, Akazawa Y, Nakayama H, et al. Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nat Commun. 2015;6:7527.

    PubMed  Article  Google Scholar 

  100. Guan Y, Wang Y, Li B, Shen K, Li Q, Ni Y, Huang L. Mitophagy in carcinogenesis, drug resistance and anticancer therapeutics. Cancer Cell Int. 2021;21:350.

    PubMed  PubMed Central  Article  Google Scholar 

  101. Hou H, Er P, Cheng J, Chen X, Ding X, Wang Y, Chen X, Yuan Z, Pang Q, Wang P, et al. High expression of FUNDC1 predicts poor prognostic outcomes and is a promising target to improve chemoradiotherapy effects in patients with cervical cancer. Cancer Med. 2017;6:1871–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Wu H, Wang T, Liu Y, Li X, Xu S, Wu C, Zou H, Cao M, Jin G, Lang J, et al. Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis. J Exp Clin Cancer Res: CR. 2020;39:274.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Yamashita K, Miyata H, Makino T, Masuike Y, Furukawa H, Tanaka K, Miyazaki Y, Takahashi T, Kurokawa Y, Yamasaki M, et al. High expression of the mitophagy-related protein Pink1 is associated with a poor response to chemotherapy and a poor prognosis for patients treated with neoadjuvant chemotherapy for esophageal squamous cell carcinoma. Ann Surg Oncol. 2017;24:4025–32.

    PubMed  Article  Google Scholar 

  104. Villa E, Proïcs E, Rubio-Patiño C, Obba S, Zunino B, Bossowski JP, Rozier RM, Chiche J, Mondragón L, Riley JS, et al. Parkin-independent mitophagy controls chemotherapeutic response in cancer cells. Cell Rep. 2017;20:2846–59.

    CAS  PubMed  Article  Google Scholar 

  105. Su Y-C, Davuluri GVN, Chen C-H, Shiau D-C, Chen C-C, Chen C-L, Lin Y-S, Chang C-P. Galectin-1-induced autophagy facilitates cisplatin resistance of hepatocellular carcinoma. PLoS ONE. 2016;11:e0148408.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. Pietrocola F, Izzo V, Niso-Santano M, Vacchelli E, Galluzzi L, Maiuri MC, Kroemer G. Regulation of autophagy by stress-responsive transcription factors. Semin Cancer Biol. 2013;23:310–22.

    CAS  PubMed  Article  Google Scholar 

  107. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, Chan DC. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell. 2010;141:280–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Patten DA, Wong J, Khacho M, Soubannier V, Mailloux RJ, Pilon-Larose K, MacLaurin JG, Park DS, McBride HM, Trinkle-Mulcahy L, et al. OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand. EMBO J. 2014;33:2676–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. da Silva Rosa SC, Martens MD, Field JT, Nguyen L, Kereliuk SM, Hai Y, Chapman D, Diehl-Jones W, Aliani M, West AR, et al. BNIP3L/Nix-induced mitochondrial fission, mitophagy, and impaired myocyte glucose uptake are abrogated by PRKA/PKA phosphorylation. Autophagy. 2021;17:2257–72.

    PubMed  Article  CAS  Google Scholar 

  110. Liu H, Ho PW-L, Leung C-T, Pang SY-Y, Chang EES, Choi ZY-K, Kung MH-W, Ramsden DB, Ho S-L. Aberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2 mice. Autophagy. 2021;17:3196–220.

  111. Bao D, Zhao J, Zhou X, Yang Q, Chen Y, Zhu J, Yuan P, Yang J, Qin T, Wan S, et al. Mitochondrial fission-induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression. Oncogene. 2019;38:5007–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Osman C, Noriega TR, Okreglak V, Fung JC, Walter P. Integrity of the yeast mitochondrial genome, but not its distribution and inheritance, relies on mitochondrial fission and fusion. Proc Natl Acad Sci USA. 2015;112:E947–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Yu Y, Peng X-D, Qian X-J, Zhang K-M, Huang X, Chen Y-H, Li Y-T, Feng G-K, Zhang H-L, Xu X-L, et al. Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis. Signal Transduct Target Ther. 2021;6:401.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J. Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA. 2011;108:10190–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Hosseinzadeh A, Bahrampour Juybari K, Kamarul T, Sharifi AM. Protective effects of atorvastatin on high glucose-induced oxidative stress and mitochondrial apoptotic signaling pathways in cultured chondrocytes. J Physiol Biochem. 2019;75:153–62.

    CAS  PubMed  Article  Google Scholar 

  116. Nanda N. Fine structure of the erythrocytic stages of Plasmodium vivax and the host cell alterations. Indian J Malariol. 1990;27:65–78.

    CAS  PubMed  Google Scholar 

  117. Han X-J, Yang Z-J, Jiang L-P, Wei Y-F, Liao M-F, Qian Y, Li Y, Huang X, Wang J-B, Xin H-B, et al. Mitochondrial dynamics regulates hypoxia-induced migration and antineoplastic activity of cisplatin in breast cancer cells. Int J Oncol. 2015;46:691–700.

    CAS  PubMed  Article  Google Scholar 

  118. Chen X, Glytsou C, Zhou H, Narang S, Reyna DE, Lopez A, Sakellaropoulos T, Gong Y, Kloetgen A, Yap YS, et al. Targeting mitochondrial structure sensitizes acute myeloid leukemia to venetoclax treatment. Cancer Discov. 2019;9:890–909.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Song J, Zhao W, Lu C, Shao X. LATS2 overexpression attenuates the therapeutic resistance of liver cancer HepG2 cells to sorafenib-mediated death via inhibiting the AMPK-Mfn2 signaling pathway. Cancer Cell Int. 2019;19:60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Decker CW, Garcia J, Gatchalian K, Arceneaux D, Choi C, Han D, Hernandez JB. Mitofusin-2 mediates doxorubicin sensitivity and acute resistance in Jurkat leukemia cells. Biochem Biophys Rep. 2020;24:100824.

    PubMed  PubMed Central  Google Scholar 

  121. Wang W-J, Lai H-Y, Zhang F, Shen W-J, Chu P-Y, Liang H-Y, Liu Y-B, Wang J-M. MCL1 participates in leptin-promoted mitochondrial fusion and contributes to drug resistance in gallbladder cancer. JCI Insight. 2021;6.

  122. Li S, Wu Y, Ding Y, Yu M, Ai Z. CerS6 regulates cisplatin resistance in oral squamous cell carcinoma by altering mitochondrial fission and autophagy. J Cell Physiol. 2018;233:9416–25.

    CAS  PubMed  Article  Google Scholar 

  123. Tomková V, Sandoval-Acuña C, Torrealba N, Truksa J. Mitochondrial fragmentation, elevated mitochondrial superoxide and respiratory supercomplexes disassembly is connected with the tamoxifen-resistant phenotype of breast cancer cells. Free Radic Biol Med. 2019;143:510–21.

    PubMed  Article  CAS  Google Scholar 

  124. Cai J, Wang J, Huang Y, Wu H, Xia T, Xiao J, Chen X, Li H, Qiu Y, Wang Y, et al. ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells. Cell Death Dis. 2016;7:e2459.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Huang Q, Zhan L, Cao H, Li J, Lyu Y, Guo X, Zhang J, Ji L, Ren T, An J, et al. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 2016;12.

  126. Han Y, Cho U, Kim S, Park IS, Cho JH, Dhanasekaran DN, Song YS. Tumour microenvironment on mitochondrial dynamics and chemoresistance in cancer. Free Radical Res. 2018;52:1271–87.

    CAS  Article  Google Scholar 

  127. Csordás G, Weaver D, Hajnóczky G. Endoplasmic reticulum-mitochondrial contactology: structure and signaling functions. Trends Cell Biol. 2018;28:523–40.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  128. Dia M, Gomez L, Thibault H, Tessier N, Leon C, Chouabe C, Ducreux S, Gallo-Bona N, Tubbs E, Bendridi N, et al. Reduced reticulum-mitochondria Ca transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy. Basic Res Cardiol. 2020;115:74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Horvath SE, Daum G. Lipids of mitochondria. Prog Lipid Res. 2013;52:590–614.

    CAS  PubMed  Article  Google Scholar 

  130. Acoba MG, Senoo N, Claypool SM. Phospholipid ebb and flow makes mitochondria go. J Cell Biol. 2020;219.

  131. Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis. Cell. 2015;163:560–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Zhou B, Zhang J-Y, Liu X-S, Chen H-Z, Ai Y-L, Cheng K, Sun R-Y, Zhou D, Han J, Wu Q. Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res. 2018;28:1171–85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. Lewis SC, Uchiyama LF, Nunnari J. ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science (New York, NY). 2016;353:aaf5549.

  134. Yang M, Li C, Sun L. Mitochondria-associated membranes (MAMs): a novel therapeutic target for treating metabolic syndrome. Curr Med Chem. 2021;28:1347–62.

    CAS  PubMed  Article  Google Scholar 

  135. Büsselberg D, Florea A-M. Targeting intracellular calcium signaling ([Ca]) to overcome acquired multidrug resistance of cancer cells: a mini-overview. Cancers. 2017;9.

  136. Genovese I, Carinci M, Modesti L, Aguiari G, Pinton P, Giorgi C. Mitochondria: insights into crucial features to overcome cancer chemoresistance. Int J Mol Sci. 2021;22.

  137. Ren T, Wang J, Zhang H, Yuan P, Zhu J, Wu Y, Huang Q, Guo X, Zhang J, Ji L, et al. MCUR1-mediated mitochondrial calcium signaling facilitates cell survival of hepatocellular carcinoma via reactive oxygen species-dependent P53 degradation. Antioxid Redox Signal. 2018;28:1120–36.

    CAS  PubMed  Article  Google Scholar 

  138. Chen L, Sun Q, Zhou D, Song W, Yang Q, Ju B, Zhang L, Xie H, Zhou L, Hu Z, et al. HINT2 triggers mitochondrial Ca influx by regulating the mitochondrial Ca uniporter (MCU) complex and enhances gemcitabine apoptotic effect in pancreatic cancer. Cancer Lett. 2017;411:106–16.

    CAS  PubMed  Article  Google Scholar 

  139. Hall DD, Wu Y, Domann FE, Spitz DR, Anderson ME. Mitochondrial calcium uniporter activity is dispensable for MDA-MB-231 breast carcinoma cell survival. PLoS ONE. 2014;9: e96866.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. Marchi S, Lupini L, Patergnani S, Rimessi A, Missiroli S, Bonora M, Bononi A, Corrà F, Giorgi C, De Marchi E, et al. Downregulation of the mitochondrial calcium uniporter by cancer-related miR-25. Current biology : CB. 2013;23:58–63.

    CAS  PubMed  Article  Google Scholar 

  141. Zeng F, Chen X, Cui W, Wen W, Lu F, Sun X, Ma D, Yuan Y, Li Z, Hou N, et al. RIPK1 Binds MCU to mediate induction of mitochondrial Ca uptake and promotes colorectal oncogenesis. Can Res. 2018;78:2876–85.

    CAS  Article  Google Scholar 

  142. de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 2008;456:605–10.

    PubMed  Article  CAS  Google Scholar 

  143. Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK. ER tubules mark sites of mitochondrial division. Science (New York, NY). 2011;334:358–62.

    CAS  Article  Google Scholar 

  144. Rambold AS, Cohen S, Lippincott-Schwartz J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev Cell. 2015;32:678–92.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. van Bergeijk P, Hoogenraad CC, Kapitein LC. Right time, right place: probing the functions of organelle positioning. Trends Cell Biol. 2016;26:121–34.

    PubMed  Article  Google Scholar 

  146. Lu L, Zhang J, Gan P, Wu L, Zhang X, Peng C, Zhou J, Chen X, Su J. Novel functions of CD147 in the mitochondria exacerbates melanoma metastasis. Int J Biol Sci. 2021;17:285–97.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Wang X, Chang X, He C, Fan Z, Yu Z, Yu B, Wu X, Hou J, Li J, Su L, et al. ATP5B promotes the metastasis and growth of gastric cancer by activating the FAK/AKT/MMP2 pathway. FASEB J. 2021;35:e20649.

    CAS  PubMed  Google Scholar 

  148. Caino MC, Ghosh JC, Chae YC, Vaira V, Rivadeneira DB, Faversani A, Rampini P, Kossenkov AV, Aird KM, Zhang R, et al. PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. Proc Natl Acad Sci USA. 2015;112:8638–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. Seo JH, Agarwal E, Bryant KG, Caino MC, Kim ET, Kossenkov AV, Tang H-Y, Languino LR, Gabrilovich DI, Cohen AR, et al. Syntaphilin ubiquitination regulates mitochondrial dynamics and tumor cell movements. Can Res. 2018;78:4215–28.

    CAS  Article  Google Scholar 

  150. Caino MC, Seo JH, Wang Y, Rivadeneira DB, Gabrilovich DI, Kim ET, Weeraratna AT, Languino LR, Altieri DC. Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer. J Clin Invest. 2017;127:3755–69.

    PubMed  PubMed Central  Article  Google Scholar 

  151. Jung J-U, Ravi S, Lee DW, McFadden K, Kamradt ML, Toussaint LG, Sitcheran R. NIK/MAP3K14 regulates mitochondrial dynamics and trafficking to promote cell invasion. Curr Biol. 2016;26:3288–302.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Yi M, Weaver D, Hajnóczky G. Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. J Cell Biol. 2004;167:661–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. Schuler M-H, Lewandowska A, Caprio GD, Skillern W, Upadhyayula S, Kirchhausen T, Shaw JM, Cunniff B. Miro1-mediated mitochondrial positioning shapes intracellular energy gradients required for cell migration. Mol Biol Cell. 2017;28:2159–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Nguyen TT, Oh SS, Weaver D, Lewandowska A, Maxfield D, Schuler M-H, Smith NK, Macfarlane J, Saunders G, Palmer CA, et al. Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc Natl Acad Sci USA. 2014;111:E3631–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Alshaabi H, Shannon N, Gravelle R, Milczarek S, Messier T, Cunniff B. Miro1-mediated mitochondrial positioning supports subcellular redox status. Redox Biol. 2021;38: 101818.

    CAS  PubMed  Article  Google Scholar 

  156. Caino MC, Chae YC, Vaira V, Ferrero S, Nosotti M, Martin NM, Weeraratna A, O’Connell M, Jernigan D, Fatatis A, et al. Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells. J Clin Investig. 2013;123:2907–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Desai SP, Bhatia SN, Toner M, Irimia D. Mitochondrial localization and the persistent migration of epithelial cancer cells. Biophys J. 2013;104:2077–88.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Wanka H, Lutze P, Staar D, Albers A, Bäumgen I, Grunow B, Peters J. Non-secretory renin reduces oxidative stress and increases cardiomyoblast survival during glucose and oxygen deprivation. Sci Rep. 2020;10:2329.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. Onodera Y, Nam J-M, Horikawa M, Shirato H, Sabe H. Arf6-driven cell invasion is intrinsically linked to TRAK1-mediated mitochondrial anterograde trafficking to avoid oxidative catastrophe. Nat Commun. 2018;9:2682.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. Altieri DC. Mitochondria on the move: emerging paradigms of organelle trafficking in tumour plasticity and metastasis. Br J Cancer. 2017;117:301–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Dong L-F, Kovarova J, Bajzikova M, Bezawork-Geleta A, Svec D, Endaya B, Sachaphibulkij K, Coelho AR, Sebkova N, Ruzickova A, et al. Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. eLife. 2017;6.

  162. Levoux J, Prola A, Lafuste P, Gervais M, Chevallier N, Koumaiha Z, Kefi K, Braud L, Schmitt A, Yacia A, et al. Platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming. Cell Metab. 2021;33.

  163. Liu D, Gao Y, Liu J, Huang Y, Yin J, Feng Y, Shi L, Meloni BP, Zhang C, Zheng M, et al. Intercellular mitochondrial transfer as a means of tissue revitalization. Signal Transduct Target Ther. 2021;6:65.

    PubMed  PubMed Central  Article  Google Scholar 

  164. Li H, Wang C, He T, Zhao T, Chen Y-Y, Shen Y-L, Zhang X, Wang L-L. Mitochondrial transfer from bone marrow mesenchymal stem cells to motor neurons in spinal cord injury rats via gap junction. Theranostics. 2019;9:2017–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, Rowlands DJ, Quadri SK, Bhattacharya S, Bhattacharya J. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18:759–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. Dutra Silva J, Su Y, Calfee CS, Delucchi KL, Weiss D, McAuley DF, O'Kane C, Krasnodembskaya AD. Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS. Eur Respir J. 2021;58.

  167. Jackson MV, Morrison TJ, Doherty DF, McAuley DF, Matthay MA, Kissenpfennig A, O’Kane CM, Krasnodembskaya AD. Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells (Dayton, Ohio). 2016;34:2210–23.

    CAS  Article  Google Scholar 

  168. Nasoni MG, Carloni S, Canonico B, Burattini S, Cesarini E, Papa S, Pagliarini M, Ambrogini P, Balduini W, Luchetti F. Melatonin reshapes the mitochondrial network and promotes intercellular mitochondrial transfer via tunneling nanotubes after ischemic-like injury in hippocampal HT22 cells. J Pineal Res. 2021;71: e12747.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. Griessinger E, Moschoi R, Biondani G, Peyron J-F. Mitochondrial transfer in the leukemia microenvironment. Trends Cancer. 2017;3:828–39.

    CAS  PubMed  Article  Google Scholar 

  170. Shanmughapriya S, Langford D, Natarajaseenivasan K. Inter and Intracellular mitochondrial trafficking in health and disease. Ageing Res Rev. 2020;62: 101128.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. Tan AS, Baty JW, Dong L-F, Bezawork-Geleta A, Endaya B, Goodwin J, Bajzikova M, Kovarova J, Peterka M, Yan B, et al. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab. 2015;21:81–94.

    CAS  PubMed  Article  Google Scholar 

  172. Pasquier J, Guerrouahen BS, Al Thawadi H, Ghiabi P, Maleki M, Abu-Kaoud N, Jacob A, Mirshahi M, Galas L, Rafii S, et al. Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J Transl Med. 2013;11:94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A. 2006;103:1283–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Moschoi R, Imbert V, Nebout M, Chiche J, Mary D, Prebet T, Saland E, Castellano R, Pouyet L, Collette Y, et al. Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood. 2016;128:253–64.

    CAS  PubMed  Article  Google Scholar 

  175. Marlein CR, Piddock RE, Mistry JJ, Zaitseva L, Hellmich C, Horton RH, Zhou Z, Auger MJ, Bowles KM, Rushworth SA. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res. 2019;79:2285–97.

    CAS  PubMed  Article  Google Scholar 

  176. Marlein CR, Zaitseva L, Piddock RE, Robinson SD, Edwards DR, Shafat MS, Zhou Z, Lawes M, Bowles KM, Rushworth SA. NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood. 2017;130:1649–60.

    CAS  PubMed  Article  Google Scholar 

  177. Patheja P, Sahu K. Macrophage conditioned medium induced cellular network formation in MCF-7 cells through enhanced tunneling nanotube formation and tunneling nanotube mediated release of viable cytoplasmic fragments. Exp Cell Res. 2017;355:182–93.

    CAS  PubMed  Article  Google Scholar 

  178. Guaragnella N, Giannattasio S, Moro L. Mitochondrial dysfunction in cancer chemoresistance. Biochem Pharmacol. 2014;92:62–72.

    CAS  PubMed  Article  Google Scholar 

  179. Gustafsson CM, Falkenberg M, Larsson N-G. Maintenance and expression of mammalian mitochondrial DNA. Annu Rev Biochem. 2016;85:133–60.

    CAS  PubMed  Article  Google Scholar 

  180. Tigano M, Vargas DC, Tremblay-Belzile S, Fu Y, Sfeir A. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature. 2021;591:477–81.

    CAS  PubMed