Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia

Abstract Targeting mitochondrial oxidative phosphorylation (OxPhos) has become a recurring strategy in the treatment of cancer, particularly in acute myeloid leukemia (AML). Early reports suggested that leukemic blasts, and especially leukemia stem cells, depend disproportionately on mitochondrial respiration, implying a therapeutic window for systemic inhibition of the electron transport system (ETS) and OxPhos. Yet, the clinical record of broad OxPhos inhibition has been disappointing. In the present review, we argue that the pivotal question is not whether mitochondria matter for cancer, but whether specific mitochondrial processes are disproportionately essential to malignant cells compared with the organism’s most OxPhos-dependent organs. We clarify what OxPhos is (and is not), emphasizing why oxygen consumption rate (OCR) is an incomplete surrogate for ATP-producing OxPhos flux and why transcriptomic ‘OxPhos signatures’ often confound energetic demand with compensatory responses to mitochondrial damage. We then benchmark OxPhos capacity and flux across normal tissues versus tumors, highlighting that highly oxidative organs typically operate at far higher respiratory flux than most cancers. Using the Complex I inhibitor IACS-010759 as a case study, we discuss why systemic ETS inhibition predictably collided with dose-limiting toxicity. Finally, focusing on AML, we dissect how OxPhos ‘dependency’ was inferred from indirect assays, how the failure to normalize for mitochondrial content may invert conclusions, and how ATP synthase reversal can masquerade as ‘ATP-linked respiration.’ We conclude with practical criteria for identifying mitochondrial liabilities that are targetable rather than merely essential, and we outline alternative strategies, which may better align mitochondrial biology with a realistic therapeutic index.