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Thus, we hypothesized AML cells may resist chemotherapy-induced cell death by reversing the ATP synthase reaction. In support, BCL-2 inhibition with venetoclax abolished OxPhos flux without affecting mitochondrial polarization. In surviving AML cells, sustained mitochondrial polarization depended on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to down-regulations in the endogenous F\n                    <jats:sub>1<\/jats:sub>\n                    -ATPase inhibitor ATP5IF1. Knockdown of ATP5IF1 conferred venetoclax resistance, while ATP5IF1 overexpression impaired F\n                    <jats:sub>1<\/jats:sub>\n                    -ATPase activity and heightened sensitivity to venetoclax. These data identify matrix ATP consumption as a cancer cell\u2013intrinsic bioenergetic vulnerability actionable in the context of BCL-2 targeted chemotherapy.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adu5511","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T13:58:41Z","timestamp":1744207121000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":26,"title":["Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0587-5370","authenticated-orcid":true,"given":"James T.","family":"Hagen","sequence":"first","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA."},{"name":"East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, 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