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The regulation of mitochondrial dynamics in leukemic cells is therefore essential for maintaining mitochondrial homeostasis. However, the mechanisms that enable selective degradation of damaged mitochondria (mitophagy) are still poorly understood in AML. In this study, we sought to elucidate the role of PTEN-induced putative kinase 1 (PINK1), a key sensor of mitochondrial stress, in regulating mitophagy in leukemic cells. Our results identified PINK1 as a central modulator of mitophagy. Genetic depletion of PINK1 reduced both basal and stress-induced mitophagy, leading to mitochondria accumulation and functional impairment. Additionally, we discovered that PINK1 stabilization during mitochondrial stress is regulated by Prohibitin 2 (PHB2), and that depletion or inhibition of PHB2 mirrored the biological effects of PINK1 loss. Notably, both genetic depletion of PINK1 or PHB2, as well as pharmacological inhibition of PHB2, significantly increased AML cell sensitivity to venetoclax both in vitro and in vivo. Together, these findings highlight the potential of targeting the PHB2\/PINK1 signalling pathway to improve the efficacy of venetoclax-based therapies in AML by disrupting the mitophagy process.<\/jats:p>","DOI":"10.1038\/s41375-026-03160-5","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T08:08:48Z","timestamp":1791878928000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of PHB2\/PINK1-mediated mitophagy potentiates venetoclax activity in acute myeloid leukemia"],"prefix":"10.1038","author":[{"given":"Romain","family":"Vazquez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Sajot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jad","family":"Nasrallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudy","family":"Birsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1839-8411","authenticated-orcid":false,"given":"Isma\u00ebl","family":"Boussaid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8150-9959","authenticated-orcid":false,"given":"Morgane","family":"Plevenage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zubaidan","family":"Tuerdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axelle","family":"Guedon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilia","family":"Cantero Aguilar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Huynh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natacha","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chlo\u00e9","family":"Friedrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Grignano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Decroocq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7866-2571","authenticated-orcid":false,"given":"Lise","family":"Willems","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole","family":"Almire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7918-1216","authenticated-orcid":false,"given":"Marie-Clotilde","family":"Alves-Guerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyne","family":"Lauret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Simoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5492-6349","authenticated-orcid":false,"given":"Michaela","family":"Fontenay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6021-4057","authenticated-orcid":false,"given":"Olivier","family":"Kosmider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Bouscary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clement","family":"Larrue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0601-3948","authenticated-orcid":false,"given":"Nicolas","family":"Chapuis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"key":"3160_CR1","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1182\/blood.2022016867","volume":"140","author":"H D\u00f6hner","year":"2022","unstructured":"D\u00f6hner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. 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