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- Title
TRPC3 shapes the ER-mitochondria Ca<sup>2+</sup> transfer characterizing tumour-promoting senescence.
- Authors
Farfariello, Valerio; Gordienko, Dmitri V.; Mesilmany, Lina; Touil, Yasmine; Germain, Emmanuelle; Fliniaux, Ingrid; Desruelles, Emilie; Gkika, Dimitra; Roudbaraki, Morad; Shapovalov, George; Noyer, Lucile; Lebas, Mathilde; Allart, Laurent; Zienthal-Gelus, Nathalie; Iamshanova, Oksana; Bonardi, Franck; Figeac, Martin; Laine, William; Kluza, Jerome; Marchetti, Philippe
- 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 Ca2+ load via negative regulation of IP3 receptor-mediated Ca2+ release, is down regulated in senescence regardless of the type of senescence inducer. This remodelling promotes cytosolic/mitochondrial Ca2+ oscillations and elevates mitochondrial Ca2+ load, mitochondrial oxygen consumption rate and oxidative phosphorylation. Re-expression of TRPC3 in senescent cells diminishes mitochondrial Ca2+ 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. Mitochondrial Ca2+ homeostasis is reported to influence cellular senescence. Here the authors show that TRPC3 limits senescence by inhibiting IP3R-mediated Ca2+ release and ER mitochondria Ca2+ transfer and that the downregulation of TRPC3 in stromal cells affects SASP production and tumour progression.
- Subjects
CANCER cell proliferation; CELLULAR aging; STROMAL cells; OXIDATIVE phosphorylation; OXYGEN consumption; AGING
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-28597-x