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Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55\u03b1\/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55\u03b1 determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the insult, ULK1 is released from the inhibitory regulation of PP2A-B55\u03b1, whereas 2 to 4 hours later, PP2A-B55\u03b1 promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55\u03b1 controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1\u03b1 inhibitor PARIS. PP2A-B55\u03b1 targeting rescues neurodegenerative phenotypes in a fly model of Parkinson\u2019s disease, thus suggesting potential therapeutic application.<\/jats:p>","DOI":"10.1126\/sciadv.adw7376","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T17:59:16Z","timestamp":1759514356000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["The PP2A-B55\u03b1 phosphatase is a master regulator of mitochondrial degradation and biogenesis"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3857-9463","authenticated-orcid":true,"given":"Valentina","family":"Cianfanelli","sequence":"first","affiliation":[{"name":"Department of Science, University \u201cRoma TRE\u201d, Rome, Italy."},{"name":"Gynecologic Oncology Unit, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 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