2. Academic Validation
  3. Cyclophilin D plays a critical role in the survival of senescent cells

Cyclophilin D plays a critical role in the survival of senescent cells

  • EMBO J. 2024 Oct 24. doi: 10.1038/s44318-024-00259-2.
Margherita Protasoni 1 2,  Vanessa López-Polo 1,  Camille Stephan-Otto Attolini 1,  Julian Brandariz 3,  Nicolas Herranz 3 4,  Joaquin Mateo 3 5,  Sergio Ruiz 6,  Oscar Fernandez-Capetillo 7 8,  Marta Kovatcheva 9 10,  Manuel Serrano 11 12
Affiliations

Affiliations

  • 1 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.
  • 2 Cambridge Institute of Science, Altos Labs, Granta Park, Cambridge, CB21 6GP, UK.
  • 3 Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 4 Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain.
  • 5 Vall d'Hebron University Hospital, Barcelona, Spain.
  • 6 Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20814, USA.
  • 7 Spanish National Cancer Research Center (CNIO), 28028, Madrid, Spain.
  • 8 Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
  • 9 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain. marta.kovatcheva@ifom.eu.
  • 10 IFOM ETS-The AIRC Institute of Molecular Oncology, Milan, Italy. marta.kovatcheva@ifom.eu.
  • 11 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain. mserrano@altoslabs.com.
  • 12 Cambridge Institute of Science, Altos Labs, Granta Park, Cambridge, CB21 6GP, UK. mserrano@altoslabs.com.
PMID: 39448884 DOI: 10.1038/s44318-024-00259-2
Abstract

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 CA2+ 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 CA2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial CA2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.

Keywords

Cellular Senescence; Cyclophilin D; Mitochondria; Senolytic Therapy; mPTP Flickering.

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