Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria.
Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria.
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DOI：
10.1016/j.cell.2010.06.007
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发表时间：
2010-07-23
期刊：
影响因子：
64.5
通讯作者：
Foskett JK
中科院分区：
文献类型：
--
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
调节细胞代谢的机制是所有细胞的基本要求。大多数真核细胞依靠有氧线粒体代谢产生ATP。然而，线粒体活性的调节并不完全清楚。在这里，我们确定了一个意想不到的和必不可少的作用，组成型InsP3R介导的Ca2+释放在维持细胞的生物能量。巨自噬为真核生物提供了一种对营养剥夺的适应性反应，从而提高了生存率。组成型InsP3R Ca2+信号传导是营养丰富培养基中细胞中大自噬抑制所必需的。在它的情况下，细胞变得代谢受损，由于减少线粒体Ca2+摄取。InsP3R释放的Ca2+的线粒体摄取是通过提供足够的还原当量以支持氧化磷酸化来提供最佳生物能学的基本要求。这种Ca2+转移的缺乏导致丙酮酸脱氢酶的磷酸化增强和AMPK的活化，AMPK活化促存活的巨自噬。因此，组成型InsP3R Ca2+释放到线粒体是有效的线粒体呼吸和维持正常细胞生物能量所需的基本细胞过程。
Mechanisms that regulate cellular metabolism are a fundamental requirement of all cells. Most eukaryotic cells rely on aerobic mitochondrial metabolism to generate ATP. Nevertheless, regulation of mitochondrial activity is incompletely understood. Here we identified an unexpected and essential role for constitutive InsP3R-mediated Ca2+ release in maintaining cellular bioenergetics. Macroautophagy provides eukaryotes with an adaptive response to nutrient deprivation that prolongs survival. Constitutive InsP3R Ca2+ signaling is required for macroautophagy suppression in cells in nutrient-replete media. In its absence, cells become metabolically compromised due to diminished mitochondrial Ca2+ uptake. Mitochondrial uptake of InsP3R released Ca2+ is fundamentally required to provide optimal bioenergetics by providing sufficient reducing equivalents to support oxidative phosphorylation. Absence of this Ca2+ transfer results in enhanced phosphorylation of pyruvate dehydrogenase and activation of AMPK, which activates pro-survival macroautophagy. Thus, constitutive InsP3R Ca2+ release to mitochondria is an essential cellular process that is required for efficient mitochondrial respiration and maintenance of normal cell bioenergetics.
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