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

Abstract

Senescencia celular; Ciclofilina D; Mitocondrias

Senescència cel·lular; Ciclofilina D; Mitocondris

Cellular senescence; Cyclophilin D; Mitochondria

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.

MP was supported by the European Union’s Horizon 2021 research and innovation programme under the Marie Sklodowska-Curie grant agreement (HORIZON-MSCA-2021-PF-01) and the Barcelona Institute of Science and Technology (BIST). VLP was recipient of a predoctoral contract from Spanish Ministry of Education (FPU-18/05917). JB, NH, and JM work was funded by the Asociación Española Contra el Cancer (AECC; PRYCO211023SERR) and by the Instituto de Salud Carlos III (CP19/00170). SR was funded by the NIH Intramural Research Program. MK was funded by the Barcelona Institute of Science and technology (BIST) and Asociación Española Contra el Cáncer (AECC; POSTD18020SERR) and supported by the European Molecular Biology Organization (EMBO). Work in the laboratory of MS was funded by the IRB and “laCaixa” Foundation, by a Coordinated-AECC grant (PRYCO211023SERR), and by Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282).