Products Cited in Publications Worldwide Cyclophilin D plays a critical role in the survival of senescent cells

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

Protasoni, Margherita; López-Polo, Vanessa; Stephan-Otto Attolini, Camille; Brandariz, Julian; Herranz, Nicolas; Mateo, Joaquin; Ruiz, Sergio; Fernandez-Capetillo, Oscar; Kovatcheva, Marta; Serrano, Manuel

DOI: PMID:

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 , 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 ; ; Senolytic Therapy ; Cyclophilin D ; Flickering

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