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

Dorian V. Ziegler, David Vindrieux, Delphine Goehrig, Sara Jaber, Guillaume Collin, Audrey Griveau, Clotilde Wiel, Nadia Bendridi, Sophia Djebali, Valerio Farfariello, Natacha Prevarskaya, Léa Payen, Jacqueline Marvel, Sébastien Aubert, Jean-Michel Flaman, Jennifer Rieusset, Nadine Martin and David Bernard ()
Additional contact information
Dorian V. Ziegler: Université de Lyon
David Vindrieux: Université de Lyon
Delphine Goehrig: Université de Lyon
Sara Jaber: Université de Lyon
Guillaume Collin: Université de Lyon
Audrey Griveau: Université de Lyon
Clotilde Wiel: Université de Lyon
Nadia Bendridi: Lyon 1 University, INRA U1397
Sophia Djebali: Université de Lyon, Université Claude Bernard Lyon 1
Valerio Farfariello: Université des Sciences et Technologies de Lille
Natacha Prevarskaya: Université des Sciences et Technologies de Lille
Léa Payen: Université de Lyon
Jacqueline Marvel: Université de Lyon, Université Claude Bernard Lyon 1
Sébastien Aubert: Université de Lille
Jean-Michel Flaman: Université de Lyon
Jennifer Rieusset: Lyon 1 University, INRA U1397
Nadine Martin: Université de Lyon
David Bernard: Université de Lyon

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-20993-z

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