Cyclophilin D plays a critical role in the survival of senescent cells
Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca<sup>2+</sup> and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca<sup>2+</sup> influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca<sup>2+</sup> ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.
Authors
- Óscar Fernández-Capetillo (ORCID: https://orcid.org/0000-0002-2690-6885)
- Vanessa López-Polo (ORCID: https://orcid.org/0000-0001-6165-2510)
- Margherita Protasoni (ORCID: https://orcid.org/0000-0001-6557-461X)
- Joaquı́n Mateo (ORCID: https://orcid.org/0000-0001-5336-2548)
- Julian Brandariz (ORCID: https://orcid.org/0009-0006-4316-3952)
- Sergio Ruiz (ORCID: https://orcid.org/0000-0002-0177-6965)
- Manuel Serrano (ORCID: https://orcid.org/0000-0001-7177-9312)
- Nicolás Herranz (ORCID: https://orcid.org/0000-0003-1351-7300)
- Marta Kovatcheva (ORCID: https://orcid.org/0000-0002-2536-1043)
- Camille Stephan‐Otto Attolini (ORCID: https://orcid.org/0000-0001-8045-320X)
Institutions
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Spanish National Cancer Research Centre (ES)
- Vall d'Hebron Institut de Recerca (ES)
- Granta Design (United Kingdom) (GB)
- IFOM (IT)
- Institute for Research in Biomedicine (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Barcelona Institute of Science and Technology (ES)
- National Cancer Institute (US)
- Vall d'Hebron Institute of Oncology (ES)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-10-24
- DOI
- https://doi.org/10.1038/s44318-024-00259-2
- Citations
- 23
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 5.38
Funders
- European Molecular Biology Organization
- “la Caixa” Foundation
- Ministerio de Ciencia, Innovación y Universidades
- Centres de Recerca de Catalunya
- Barcelona Institute of Science and Technology
- Fundación Científica Asociación Española Contra el Cáncer
- Instituto de Salud Carlos III
- HORIZON EUROPE Marie Sklodowska-Curie Actions