TRPC3 shapes the ER-mitochondria Ca 2+ transfer characterizing tumour-promoting senescence

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 senes...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications 2022-02, Vol.13 (1), p.956
Main 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, Quesnel, Bruno, Metzger, Daniel, Bernard, David, Parys, Jan B, Lemonnier, Loïc, Prevarskaya, Natalia
Format: Article
Language:English
Subjects:
Calcium - metabolism
Carcinogenesis - pathology
Cell Line, Tumor
Cell Proliferation
Cellular Senescence
Endoplasmic Reticulum - metabolism
HEK293 Cells
Humans
Inositol 1,4,5-Trisphosphate Receptors - metabolism
Mitochondria - metabolism
Neoplasms - pathology
Oxidative Phosphorylation
Primary Cell Culture
TRPC Cation Channels - metabolism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2041-1723