Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death
Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death
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DOI：
10.1038/sj.embor.7401062
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发表时间：
2007-10-01
期刊：
影响因子：
7.7
通讯作者：
Strack, Stefan
中科院分区：
文献类型：
--
作者：
Cribbs, J. Thomas;Strack, Stefan
相反的线粒体分裂和融合反应决定了线粒体的形状和相互连接。动力蛋白相关蛋白1（Drp1）是一种古老的机械酶，它利用GTP水解来为线粒体的收缩和分裂提供动力。虽然Drp1介导的线粒体片段化被认为是凋亡程序中的早期事件，但对Drp1活性的急性调节知之甚少。在这里，我们确定了一个重要的磷酸化位点，是保守的所有后生动物Drp1直系同源物。Ser656被环腺苷酸依赖性蛋白激酶磷酸化，并被钙调神经磷酸酶去磷酸化，其磷酸化状态受交感神经张力、钙水平和细胞活力控制。通过Ser656突变为天冬氨酸的Drp1的假磷酸化导致线粒体延长并赋予对各种促凋亡损伤的抗性。相反，组成性去磷酸化Ser656Ala突变体Drp1促进线粒体碎片化，增加细胞的脆弱性。因此，Drp1在Ser656处的磷酸化提供了一种在线粒体形状、凋亡和线粒体功能的其他方面的控制中整合cAMP和钙信号的机制。
Opposing mitochondrial fission and fusion reactions determine the shape and interconnectivity of mitochondria. Dynamin-related protein 1 ( Drp1) is an ancient mechanoenzyme that uses GTP hydrolysis to power the constriction and division of mitochondria. Although Drp1-mediated mitochondrial fragmentation is recognized as an early event in the apoptotic programme, acute regulation of Drp1 activity is poorly understood. Here, we identify a crucial phosphorylation site that is conserved in all metazoan Drp1 orthologues. Ser 656 is phosphorylated by cyclic AMP-dependent protein kinase and dephosphorylated by calcineurin, and its phosphorylation state is controlled by sympathetic tone, calcium levels and cell viability. Pseudophosphorylation of Drp1 by mutation of Ser656 to aspartic acid leads to the elongation of mitochondria and confers resistance to various pro-apoptotic insults. Conversely, the constitutively dephosphorylated Ser656Ala mutant Drp1 promotes mitochondrial fragmentation and increases cell vulnerability. Thus, Drp1 phosphorylation at Ser656 provides a mechanism for the integration of cAMP and calcium signals in the control of mitochondrial shape, apoptosis and other aspects of mitochondrial function.