Nature Communications · Feb 17, 2022

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

By Farfariello V, Gordienko DV, Mesilmany L et al.

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.

doi.org/10.1038/s41467-022-28597-xOpen accessPubMed 35177596Mechanisms