Fig. 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