The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis
Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α 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-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS. PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.
Authors
- Chiara Di Malta (ORCID: https://orcid.org/0000-0001-6524-4354)
- Arnaldur Hall (ORCID: https://orcid.org/0000-0001-6847-4438)
- David Sumpton (ORCID: https://orcid.org/0000-0002-9004-4079)
- Franco Locatelli (ORCID: https://orcid.org/0000-0002-7976-3654)
- Francesco Cecconi (ORCID: https://orcid.org/0000-0002-5614-4359)
- Giacomo Milletti (ORCID: https://orcid.org/0000-0003-2391-342X)
- Sara Zanivan (ORCID: https://orcid.org/0000-0002-9880-9099)
- Shehab Ismail (ORCID: https://orcid.org/0000-0002-4150-1077)
- Apolinar Maya‐Mendoza (ORCID: https://orcid.org/0000-0001-7452-9896)
- Sofia Mauri (ORCID: https://orcid.org/0000-0003-3931-1490)
- Marco Colasanti (ORCID: https://orcid.org/0000-0002-5752-4943)
- Monica Nanni (ORCID: https://orcid.org/0000-0001-5706-0053)
- Matteo Bordi (ORCID: https://orcid.org/0000-0001-8207-8546)
- Caterina Ferraina (ORCID: https://orcid.org/0000-0002-3770-4437)
- Sérgio Lilla (ORCID: https://orcid.org/0000-0003-3142-7640)
- Ezio Giorda (ORCID: https://orcid.org/0000-0002-5875-832X)
- Alessandra Barbiera (ORCID: https://orcid.org/0000-0002-2051-2359)
- Michele Petraroia (ORCID: https://orcid.org/0009-0000-0329-1155)
- Tiziana Persichini (ORCID: https://orcid.org/0000-0001-8291-6706)
- Kenji Maeda (ORCID: https://orcid.org/0000-0002-9080-5691)
- Valentina Cianfanelli (ORCID: https://orcid.org/0000-0002-3857-9463)
- Elena Ziviani (ORCID: https://orcid.org/0000-0002-0864-8309)
- Marco Scarsella (ORCID: https://orcid.org/0000-0002-3386-9664)
- Rossella De Cegli (ORCID: https://orcid.org/0000-0002-8526-8692)
- Jiří Bártek (ORCID: https://orcid.org/0000-0003-2013-7525)
- Samantha Corrà (ORCID: https://orcid.org/0000-0003-1985-6194)
- Giulia Cadeddu (ORCID: https://orcid.org/0000-0003-1841-8395)
- Valentina Clausi (ORCID: https://orcid.org/0009-0008-2662-4774)
Institutions
- Università Cattolica del Sacro Cuore (IT)
- University of Rome Tor Vergata (IT)
- Roma Tre University (IT)
- University of Padua (IT)
- Science for Life Laboratory (SE)
- Cancer Research UK (GB)
- Agostino Gemelli University Polyclinic (IT)
- Federico II University Hospital (IT)
- Bambino Gesù Children's Hospital (IT)
- Danish Cancer Society (DK)
- Telethon Institute Of Genetics And Medicine (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Glasgow (GB)
- Sapienza University of Rome (IT)
- KU Leuven (BE)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1126/sciadv.adw7376
- Citations
- 1
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 1.35
Funders
- Dipartimenti di Eccellenza
- Cancer Research UK
- European Commission
- Danmarks Grundforskningsfond
- Novo Nordisk
- Vetenskapsrådet