TY - JOUR
T1 - Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence
AU - Wiel, Clotilde
AU - Lallet-Daher, Hélène
AU - Gitenay, Delphine
AU - Gras, Baptiste
AU - Le Calvé, Benjamin
AU - Augert, Arnaud
AU - Ferrand, Mylène
AU - Prevarskaya, Natalia
AU - Simonnet, Hélène
AU - Vindrieux, David
AU - Bernard, David
PY - 2014/5/6
Y1 - 2014/5/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84900032977&partnerID=8YFLogxK
U2 - 10.1038/ncomms4792
DO - 10.1038/ncomms4792
M3 - Article
C2 - 24797322
AN - SCOPUS:84900032977
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 3792
ER -