title: Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence.
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.
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France [5].
authors.forename: Clotilde
authors.initials: C
authors.lastname: Wiel
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France [5].
authors.forename: Hélène
authors.initials: H
authors.lastname: Lallet-Daher
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Gitenay
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Gras
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Le Calvé
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Augert
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Ferrand
authors.affiliation: Inserm U1003, Equipe labellisée par la Ligue Nationale contre le cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, F-59655 Villeneuve d'Ascq, France.
authors.forename: Natalia
authors.initials: N
authors.lastname: Prevarskaya
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Simonnet
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Vindrieux
authors.affiliation: 1] Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Senescence escape mechanisms lab, F-69000 Lyon, France [2] CNRS UMR5286, F-69000 Lyon, France [3] Centre Léon Bérard, F-69000 Lyon, France [4] Université de Lyon, F-69000 Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Bernard
mesh_terms: D002118:Calcium / Q000378:metabolism*; D016922:Cellular Senescence; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D009857:Oncogenes; D018384:Oxidative Stress
chemical_list: C506927:ITPR2 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D002118:Calcium