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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\u2019s 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 \u2018OxPhos signatures\u2019 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 \u2018dependency\u2019 was inferred from indirect assays, how the failure to normalize for mitochondrial content may invert conclusions, and how ATP synthase reversal can masquerade as \u2018ATP-linked respiration.\u2019 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.<\/jats:p>","DOI":"10.1042\/bcj20260185","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T09:33:12Z","timestamp":1778751192000},"page":"907-925","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia"],"prefix":"10.1042","volume":"483","author":[{"given":"Brett\u00a0R.","family":"Chrest","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0300-829X","authenticated-orcid":false,"given":"Kelsey\u00a0H.","family":"Fisher-Wellman","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"2026051405330914600_B1","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN","volume":"140","author":"D\u00f6hner","year":"2022","journal-title":"Blood"},{"key":"2026051405330914600_B2","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/s41419-024-06810-7","article-title":"Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia","volume":"15","author":"Nwosu","year":"2024","journal-title":"Cell Death Dis."},{"key":"2026051405330914600_B3","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1158\/2159-8290.CD-16-0313","article-title":"Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia","volume":"6","author":"Konopleva","year":"2016","journal-title":"Cancer Discov."},{"key":"2026051405330914600_B4","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and venetoclax in previously untreated acute myeloid leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N. 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