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ATP5I maintains the stability of F\u2081F\u2080-ATP synthase dimers, which is crucial for shaping cristae morphology. We demonstrate that ATP5I interacts with a biguanide analogue in vitro, and disabling its expression by CRISPR\u2013Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide-treated cells, including mitochondrial morphology alterations, reduction of the NAD\n                    <jats:sup>+<\/jats:sup>\n                    \/NADH ratio, inhibition of oxidative phosphorylation (OXPHOS), rescue of respiration by uncouplers, and a compensatory increase in glycolysis. Notably, metformin disrupts F\u2081F\u2080-ATP synthase oligomerization, leading to the accumulation of vestigial assembly intermediates in pancreatic and osteosarcoma cancer cells, a phenotype also observed upon ATP5I inactivation in pancreatic cancer cells. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and antiproliferative effects of metformin and phenformin. Finally, a genome-wide CRISPR screening in NALM-6 lymphoma cells revealed that metformin-treated cells exhibit genetic interaction profiles similar to those observed with the F\u2081F\u2080-ATP synthase inhibitor oligomycin, but not with the complex I inhibitor rotenone. This provides unbiased support for the relevance of the newly proposed target.\n                  <\/jats:p>","DOI":"10.7554\/elife.102680","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T07:25:48Z","timestamp":1734074748000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.102680","source":"Crossref","is-referenced-by-count":0,"title":["The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells"],"prefix":"10.7554","volume":"13","author":[{"given":"Guillaume","family":"Lefran\u00e7ois","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, University of Montreal","place":["Montreal, Canada"]},{"id":[{"id":"https:\/\/ror.org\/0161xgx34","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry and Molecular Medicine, CR-CHUM and Montreal Cancer Institute, 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