Oxidative Phosphorylation: Cancer & Beyond Therapeutic Target

Oxidative phosphorylation (OXPHOS) is the mitochondrial energy-conversion process in which the electron transport chain uses reducing equivalents from NADH and FADH2 to generate a proton gradient that drives ATP synthase. Cancer metabolism research initially emphasized the Warburg effect, but later studies showed that tumor cells can still depend on mitochondrial respiration to sustain ATP production, NAD+/NADH balance, aspartate synthesis, redox homeostasis, and biosynthetic demand. OXPHOS has therefore become a major research direction linking cancer metabolic reprogramming, tumor proliferation, therapy tolerance, mitochondrial dysfunction, and cell fate control^[1][2][3][4].
The mechanistic basis of OXPHOS includes complexes I-IV, coenzyme Q, cytochrome c, complex V, TCA-cycle substrate input, mitochondrial membrane potential, and reactive oxygen species production. Complex I inhibition can restrict NAD+ regeneration and aspartate production, explaining part of the sensitivity of selected cancer cells to glucose limitation, biguanides, and respiratory-chain inhibitors. OXPHOS inhibitors such as IACS-010759 exploit mitochondrial metabolic dependence in cancer models, and BCL-2 inhibition can target OXPHOS to eradicate quiescent leukemia stem cells. Disease applications include tumor metabolic vulnerability screening, drug-resistant cancer models, cancer stem cell biology, hypoxic tumor microenvironment studies, and rational metabolic combination therapy, with broader relevance to immunometabolism, inflammation, and metabolic disease. T-cell fate depends on metabolic reprogramming, and mitochondrial dynamics and OXPHOS status influence effector T cells, memory T cells, and exhaustion-associated phenotypes. Current barriers include narrow therapeutic windows, normal-tissue toxicity, compensatory metabolism, tumor heterogeneity, mitochondrial target selectivity, and insufficient predictive biomarkers; future studies should combine isotope tracing, single-cell metabolomics, spatial metabolic imaging, and mechanism-defined combination models to distinguish treatable OXPHOS dependence from nonspecific mitochondrial stress^{[5][6][7][8][9][10][11][12]}.