Résumé
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.
| langue originale | Anglais |
|---|---|
| Numéro d'article | 3792 |
| journal | Nature Communications |
| Volume | 5 |
| Les DOIs | |
| Etat de la publication | Publié - 6 mai 2014 |
Financement
We thank Stéphanie Courtois-Cox and Sarah Kabani for critical reading of the manuscript, Christophe Vanbelle, from the SFR Lyon-EST CeCILE platform, for expertise in confocal microscopy, Professor Xianhua Wang for the kind gift of plasmid pcDNA3.1 mitochondrial GCaMP2 and Professor Jan Parys and laboratory members for helpful discussions. This work was carried out with the support of the ‘Institut National du Cancer’, the ‘Ligue Nationale contre le cancer, comité de la Savoie’, the ‘Fondation ARC’, the ‘Fondation de France’ and the ‘RTRS Fondation Synergie Lyon Cancer’. C.W. is supported by the ‘Ligue national contre le Cancer’ and the ‘Fondation pour la Recherche Médicale’.