Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1α
Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1α
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DOI：
10.1038/sj.cdd.4401784
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发表时间：
2006-04-01
影响因子：
12.4
通讯作者：
Rizzuto, R
中科院分区：
文献类型：
--
作者：
Bianchi, K;Vandecasteele, G;Rizzuto, R
线粒体Ca2+摄取控制多种细胞功能，如有氧代谢，胞质Ca2+信号传导和线粒体参与凋亡。汇聚在细胞器上的调节输入可以调节这一过程，决定Ca2+介导的细胞刺激的最终结果。我们在HeLa细胞和原代骨骼肌管中研究了转录过氧化物酶体增殖激活受体- γ -共激活因子-1 α (PGC-1 α)对Ca2+信号传导的影响，PGC-1 α触发细胞器生物发生并修饰线粒体蛋白质组。PGC-1 α通过降低线粒体Ca2+摄取位点的功效和增加细胞器体积，选择性地减少线粒体Ca2+对细胞刺激的反应。反过来，这影响了HeLa细胞的ER Ca2+释放和细胞质反应。最重要的是，线粒体Ca2+摄取的调节显著降低了细胞对Ca2+介导的C-2神经酰胺促凋亡作用的敏感性。这些结果揭示了PGC-1 α在塑造线粒体参与钙信号传导中的主要作用，这是其在病理生理条件下对应激和促凋亡刺激的保护作用的基础。
Mitochondrial Ca2+ uptake controls cellular functions as diverse as aerobic metabolism, cytosolic Ca2+ signalling and mitochondrial participation in apoptosis. Modulatory inputs converging on the organelle can regulate this process, determining the final outcome of Ca2+-mediated cell stimulation. We investigated in HeLa cells and primary skeletal myotubes the effect on Ca2+ signalling of the transcriptional peroxisome-proliferator-activated-receptor-gamma-coactivator-1 alpha (PGC-1 alpha), which triggers organelle biogenesis and modifies the mitochondrial proteome. PGC-1 alpha selectively reduced mitochondrial Ca2+ responses to cell stimulation by reducing the efficacy of mitochondrial Ca2+ uptake sites and increasing organelle volume. In turn, this affected ER Ca2+ release and cytosolic responses in HeLa cells. Most importantly, the modulation of mitochondrial Ca2+ uptake significantly reduced cellular sensitivity to the Ca2+-mediated proapoptotic effect of C-2 ceramide. These results reveal a primary role of PGC-1 alpha in shaping mitochondrial participation in calcium signalling, that underlies its protective role against stress and proapoptotic stimuli in pathophysiological conditions.