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Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBP\u03b1-induced fatty acid \u03b2-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBP\u03b1 methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-\u03b3 coactivator-1 PGC1\u03b1 upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.<\/jats:p>","DOI":"10.1084\/jem.20200924","type":"journal-article","created":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T02:34:52Z","timestamp":1610418892000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":126,"title":["Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6116-981X","authenticated-orcid":true,"given":"Lucille","family":"Stuani","sequence":"first","affiliation":[{"name":"Centre de Recherches en Canc\u00e9rologie de Toulouse, Universit\u00e9 de Toulouse, Institut National de la Sant\u00e9 et de la Recherch\u00e9 M\u00e9dicale, Centre National de la Recherche Scientifique, 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