TRPC3 shapes the ER-mitochondria Ca transfer characterizing tumour-promoting senescence.
Fiche publication
Date publication
février 2022
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr METZGER Daniel
Tous les auteurs :
Farfariello V, Gordienko DV, Mesilmany L, Touil Y, Germain E, Fliniaux I, Desruelles E, Gkika D, Roudbaraki M, Shapovalov G, Noyer L, Lebas M, Allart L, Zienthal-Gelus N, Iamshanova O, Bonardi F, Figeac M, Laine W, Kluza J, Marchetti P, Quesnel B, Metzger D, Bernard D, Parys JB, Lemonnier L, Prevarskaya N
Lien Pubmed
Résumé
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 load via negative regulation of IP receptor-mediated Ca release, is down regulated in senescence regardless of the type of senescence inducer. This remodelling promotes cytosolic/mitochondrial Ca oscillations and elevates mitochondrial Ca load, mitochondrial oxygen consumption rate and oxidative phosphorylation. Re-expression of TRPC3 in senescent cells diminishes mitochondrial Ca 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.
Référence
Nat Commun. 2022 Feb 17;13(1):956