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Herein, we report MitoATP\u2010nFCM, a nano\u2010flow cytometry platform enabling single\u2010mitochondrion ATP measurement via simultaneous fluorescence and side scatter detection. We uncover 1.7\u20131.9\u2010fold higher ATP levels in isolated mitochondria from breast (MCF\u20107, MDA\u2010MB\u2010231) and colon (HCT\u201015, HCT\u2010116) cancer cells than in their normal counterparts. Single\u2010organelle analysis further reveals coordinated metabolic reprogramming in cancer mitochondria, featuring elevated membrane potential, increased ATP synthase expression, and reduced hexokinase 2 levels, demonstrating their OXPHOS\u2010dominant bioenergetic phenotype that contrasts with classical Warburg\u2010effect expectations. Furthermore, we establish a screening strategy to identify highly potent cancer\u2010selective inhibitors targeting mitochondrial metabolism. We find that bedaquiline (ATP synthase inhibitor) outperforms oligomycin A in specificity, VLX600 (electron transport chain inhibitor) shows superior selectivity to rotenone\/metformin, and CPI\u2010613 (tricarboxylic acid cycle blocker) surpasses other glutaminase inhibitors. MitoATP\u2010nFCM establishes a quantitative single\u2010organelle platform that profiles elevated mitoATP levels in cancer cells and enables precision screening of OXPHOS\u2010targeting inhibitors.<\/jats:p>","DOI":"10.1002\/advs.202513341","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T08:49:07Z","timestamp":1770972547000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single\u2010Mitochondrion ATP Profiling Directs Discovery of Targetable OXPHOS Dependency in Cancers"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4213-7303","authenticated-orcid":false,"given":"Xu","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Chemical Biology MOE Key Laboratory of Spectrochemical Analysis &amp; Instrumentation Fujian Key Laboratory of Chemical Biology (Xiamen University) State Key Laboratory of Physical Chemistry of Solid 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