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].
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.
Nat Commun. 2014 May 6;5:3792. doi: 10.1038/ncomms4792.
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.
衰老涉及各种病理生理状况。除了视网膜母细胞瘤和 p53 通路的丧失外，人们对其他参与衰老的通路知之甚少。在这里，我们确定了两种钙通道；肌醇 1,4,5-三磷酸受体，2 型（ITPR2）（也称为肌醇 1,4,5-三磷酸受体 2（IP3R2））和线粒体钙单向转运蛋白（MCU）作为功能丧失遗传筛选中的新衰老调节剂。我们表明，内质网 (ER) 钙释放的已知介质 ITPR2 的丧失，以及线粒体钙摄取所必需的 MCU 的丧失，使细胞能够逃避致癌基因诱导的衰老 (OIS)。在 OIS 期间，ITPR2 触发 ER 中的钙释放，随后通过 MCU 通道积累线粒体钙。线粒体钙的积累导致随后线粒体膜电位下降、活性氧物质积累和衰老。这种 ER-线粒体钙转运不仅限于 OIS，还参与复制性衰老。我们的研究结果表明 ITPR2 通道的钙释放及其随后在线粒体中的积累具有功能作用。
