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

Valério Farfariello ,Loïc Lemonnier,Bruno Quesnel,Emilie Desruelles,Franck Bonardi,Laurent Allart,Daniel Metzger,Jérôme Kluza ,Jan B Parys,Martin Figeac,David Bernard,Oksana Iamshanova,Lucile Noyer,Nathalie Zienthal-Gelus,Lina Mesilmany,Emmanuelle Germain,George Shapovalov,William Laine,Morad Roudbaraki,Dimitra Gkika,Dmitri Gordienko ,Yasmine Touil,Ingrid Fliniaux,Philippe Marchetti,Mathilde Lebas,Natalia Prevarskaya

doi:10.1038/s41467-022-28597-x

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.

Highlights

Cellular senescence is implicated in a great number of diseases including cancer
We demonstrate that TRPC3 protein, acting as a controller of mitochondrial Ca2+ load via negative regulation of IP3 receptormediated Ca2+ release, is down regulated in senescence regardless of the type of senescence inducer
In order to assess possible changes in the expression of Ca2+permeable channels in senescence, we used several experimental models: (1) human prostate fibroblasts (HPrFs) and prostate cancer-associated fibroblasts (CAFs) treated with docetaxel (Doce)—a microtubule poison commonly used in prostate cancer therapy[27,28] and known to induce senescence in several cell types[3,9]; (2) HPrFs treated with hydrogen peroxide, H2O229,30 and (3) MRC-5 fibroblasts in which senescence was induced by oncogenic RAS

Summary

Introduction

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 receptormediated 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. Data are expressed as mean ± SEM (n = 3). Referred to as senescence-associated secretory phenotype (SASP)[4–6], which includes secreted proteins like metalloproteases, inflammatory cytokines and growth factors

Methods

Results

Conclusion