TRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2022

TRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence

Lucile Noyer

Abstract

Abstract Cellular senescence is implicated in a great number of diseases including cancer. Although alterations in mitochondrial metabolism were reported as senescence drivers, the underlying mechanisms remain elusive. We report the mechanism altering mitochondrial function and OXPHOS in stress-induced senescent fibroblasts. We demonstrate that TRPC3 protein, acting as a controller of mitochondrial Ca 2+ load via negative regulation of IP 3 receptor-mediated Ca 2+ release, is down regulated in senescence regardless of the type of senescence inducer. This remodelling promotes cytosolic/mitochondrial Ca 2+ oscillations and elevates mitochondrial Ca 2+ load, mitochondrial oxygen consumption rate and oxidative phosphorylation. Re-expression of TRPC3 in senescent cells diminishes mitochondrial Ca 2+ load and promotes escape from OIS-induced senescence. Cellular senescence evoked by TRPC3 downregulation in stromal cells displays a proinflammatory and tumour-promoting secretome that encourages cancer epithelial cell proliferation and tumour growth in vivo. Altogether, our results unravel the mechanism contributing to pro-tumour behaviour of senescent cells.
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Dates and versions

hal-03666578 , version 1 (22-06-2023)

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Valerio Farfariello, Dmitri Gordienko, Lina Mesilmany, Yasmine Touil, Emmanuelle Germain, et al.. TRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence. Nature Communications, 2022, 13 (1), pp.956. ⟨10.1038/s41467-022-28597-x⟩. ⟨hal-03666578⟩
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