Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence.

Clotilde Wiel,Mylène Ferrand,Baptiste Gras,Hélène Simonnet,Delphine Gitenay,Arnaud Augert,Benjamin Le Calvé,David Vindrieux,David Bernard,Hélène Lallet-Daher,Natalia Prevarskaya

doi:10.1038/ncomms4792

Abstract

Senescence is involved in various pathophysiological conditions. Besides loss of retinoblastoma and p53 pathways, little is known about other pathways involved in senescence. Here we identify two calcium channels; inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) (also known as inositol 1,4,5-triphosphate receptor 2 (IP3R2)) and mitochondrial calcium uniporter (MCU) as new senescence regulators in a loss-of-function genetic screen. We show that loss of ITPR2, known to mediate endoplasmic reticulum (ER) calcium release, as well as loss of MCU, necessary for mitochondrial calcium uptake, enable escape from oncogene-induced senescence (OIS). During OIS, ITPR2 triggers calcium release from the ER, followed by mitochondrial calcium accumulation through MCU channels. Mitochondrial calcium accumulation leads to a subsequent decrease in mitochondrial membrane potential, reactive oxygen species accumulation and senescence. This ER-mitochondria calcium transport is not restricted to OIS, but is also involved in replicative senescence. Our results show a functional role of calcium release by the ITPR2 channel and its subsequent accumulation in the mitochondria.

Highlights

Senescence is involved in various pathophysiological conditions
These observations prompted us to study the role of ITPR2 in oncogene-induced senescence escape, a key step required for tumour initiation and progression
By performing quantitative reverse transcriptase-PCR, we found that ITPR1, 2 and 3 were all expressed in HEC–TM cells (Supplementary Fig. 2b)

Summary

Introduction

Senescence is involved in various pathophysiological conditions. Besides loss of retinoblastoma and p53 pathways, little is known about other pathways involved in senescence. We identify two calcium channels; inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) ( known as inositol 1,4,5-triphosphate receptor 2 (IP3R2)) and mitochondrial calcium uniporter (MCU) as new senescence regulators in a loss-of-function genetic screen. Mitochondrial calcium accumulation leads to a subsequent decrease in mitochondrial membrane potential, reactive oxygen species accumulation and senescence This ER-mitochondria calcium transport is not restricted to OIS, but is involved in replicative senescence. We identify inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) and mitochondrial calcium uniporter (MCU) as two new actors of senescence, whose knockdown results in senescence escape. Their identification sheds light on the role of calcium movement, and in particular, mitochondrial calcium accumulation in senescence induction

Methods

Results

Conclusion