Calcium channel ITPR2 and mitochondria–ER contacts promote cellular senescence and aging

Abstract

Cellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.

Cellular senescence links mitochondria-ER contacts and aging

“…In line with increased evidence of the role of calcium fluxes within the cell and specifically between ER and mitochondria 46,61,62,144,145 , calcium signalling appears to be an interesting candidate to mediate the senescence phenotype. In human endothelial cells and MEFs, replicative senescence is characterized by an increased MERCs number and a subsequent accumulation of mitochondrial calcium 46,146 . Accordingly, replicative senescent neurons display also an increased transfer of calcium from the ER to mitochondria accompanied by an upregulation of MCU expression 147 .…”

“…Concerning ITPR-GRP75-VDAC complex, GRP75 overexpression leads to increased replicative lifespan through downregulation of RAS and reduced phosphorylation of ERK2 118,119 and ITPRs promote cellular senescence 46,61,62 , as it will be further discussed below.…”

The metabolic roots of senescence: mechanisms and opportunities for intervention

“…More recent studies also showed that lowering endoplasmic reticulum (ER)-mitochondria contact by ablating the Itpr2 calcium channel in mice lowers the number of age-related senescent cells and the levels of several SASP factors, resulting in an extension of health span and lifespan 57 . However, it is unclear if these effects are due to reduced mitochondrial calcium overload, diminished ER-mitochondrial contacts, or some combination of both.…”

Caspases in the Developing Central Nervous System: Apoptosis and Beyond

“…Indeed, Ca 2+ may play a role in this respect. Aside from cytochrome c and cognate apoptogenic agents, depolarized mitochondria initiate Ca 2+ waves and trigger the depolarization of surrounding mitochondria (Pacher and Hajnóczky, 2001;Ziegler et al, 2021). Actually, the propagation of waves of released cytochrome c have been reported during apoptosis (Lartigue et al, 2008;Cheng and Ferrell, 2018).…”