The Mitochondrial Inner Membrane GTPase, Optic Atrophy 1 (Opa1), Restores Mitochondrial Morphology and Promotes Neuronal Survival following Excitotoxicity
The Mitochondrial Inner Membrane GTPase, Optic Atrophy 1 (Opa1), Restores Mitochondrial Morphology and Promotes Neuronal Survival following Excitotoxicity
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DOI：
10.1074/jbc.m110.167155
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发表时间：
2011-02-01
影响因子：
4.8
通讯作者：
Slack, Ruth S.
中科院分区：
文献类型：
--
作者：
Jahani-Asl, Arezu;Pilon-Larose, Karine;Slack, Ruth S.
线粒体动力学已被广泛研究的背景下，经典的细胞死亡模型，涉及到线粒体介导的细胞色素c的释放。兴奋性毒性神经元丢失是一种非经典的死亡信号通路，其发生在不依赖于Bax激活的谷氨酸受体过度激活之后。目前，线粒体动力学在兴奋性毒性调节中的作用在很大程度上仍然未知。在这里，我们报告说，NMDA诱导的兴奋性毒性的结果在线粒体形态的缺陷，明显的存在过多的片段化线粒体，线粒体融合的停止，嵴扩张。上调线粒体内膜GT3，Opa1，能够恢复线粒体形态和保护神经元免受兴奋性毒性损伤。Opa1在钙依赖性蛋白酶calpain的下游发挥作用。钙蛋白酶抑制剂（一种内源性钙蛋白酶抑制剂）抑制钙蛋白酶活性，可显著挽救线粒体缺陷并维持神经元存活。Opa1是钙蛋白酶抑制剂介导的神经保护所必需的，因为在NMDA诱导的毒性后发现的增强的存活率在Opa1丧失后显著降低。我们的研究结果定义了一种机制，即通过Opa1功能丧失介导的线粒体网络的崩溃导致兴奋性毒性神经元损伤后的神经元死亡。这些研究表明Opa1作为一个潜在的治疗靶点，以促进急性脑损伤和神经退行性疾病后的神经元存活。
Mitochondrial dynamics have been extensively studied in the context of classical cell death models involving Bax-mediated cytochrome c release. Excitotoxic neuronal loss is a nonclassical death signaling pathway that occurs following overactivation of glutamate receptors independent of Bax activation. Presently, the role of mitochondrial dynamics in the regulation of excitotoxicity remains largely unknown. Here, we report that NMDA-induced excitotoxicity results in defects in mitochondrial morphology as evident by the presence of excessive fragmented mitochondria, cessation of mitochondrial fusion, and cristae dilation. Up-regulation of the mitochondrial inner membrane GTPase, Opa1, is able to restore mitochondrial morphology and protect neurons against excitotoxic injury. Opa1 functions downstream of the calcium-dependent protease, calpain. Inhibition of calpain activity by calpastatin, an endogenous calpain inhibitor, significantly rescued mitochondrial defects and maintained neuronal survival. Opa1 was required for calpastatin-mediated neuroprotection because the enhanced survival found following NMDA-induced toxicity was significantly reduced upon loss of Opa1. Our results define a mechanism whereby breakdown of the mitochondrial network mediated through loss of Opa1 function contributes to neuronal death following excitotoxic neuronal injury. These studies suggest Opa1 as a potential therapeutic target to promote neuronal survival following acute brain damage and neurodegenerative diseases.