MFN2 Couples Glutamate Excitotoxicity and Mitochondrial Dysfunction in Motor Neurons
MFN2 Couples Glutamate Excitotoxicity and Mitochondrial Dysfunction in Motor Neurons
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DOI：
10.1074/jbc.m114.617167
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发表时间：
2015-01-02
影响因子：
4.8
通讯作者：
Wang, Xinglong
中科院分区：
文献类型：
--
作者：
Wang, Wenzhang;Zhang, Fan;Wang, Xinglong
背景：线粒体的功能依赖于线粒体的分裂和融合动力学。结果：钙蛋白酶介导的Mfn2降解与谷氨酸诱导的脊髓运动神经元线粒体功能障碍和神经元死亡有关。结论：钙激活酶介导的Mfn2降解是谷氨酸兴奋毒性过程中调节线粒体融合的一种新机制。意义：Mfn2可能是对抗运动神经元谷氨酸兴奋性毒性的一种新的治疗靶点。线粒体功能障碍在谷氨酸诱导的神经元兴奋性毒性中起核心作用，线粒体的分裂/融合动力学对线粒体的形态和功能至关重要。在这里，我们在脊髓运动神经元中建立了谷氨酸兴奋性毒性、线粒体动力学和线粒体功能障碍之间的一个新的机制链接器。谷氨酸诱导的神经元死亡前，半胱氨酸蛋白酶的激活可导致线粒体外膜融合调节因子丝裂蛋白2(mitofusin2，Mfn2)的降解，导致Mfn2介导的线粒体碎裂。Mfn2缺乏会损害线粒体功能，导致运动神经元死亡，并使运动神经元容易受到谷氨酸的兴奋毒性作用。相反，在体外和小鼠脊髓运动神经元中，Mfn2的过表达可以阻止谷氨酸诱导的线粒体碎裂、线粒体功能障碍和/或神经元死亡。抑制钙蛋白酶的激活也减轻了谷氨酸对线粒体和神经元的兴奋毒性。综上所述，这些结果提示，谷氨酸兴奋毒性通过钙激活酶介导的运动神经元Mfn2降解损伤线粒体动力学，从而导致线粒体功能障碍，从而存在谷氨酸兴奋毒性与线粒体功能障碍耦合的分子机制。
Background: Mitochondrial function is dependent on mitochondrial fission and fusion dynamics. Results: Calpain-mediated degradation of MFN2 is responsible for glutamate-induced mitochondrial dysfunction and neuronal death in spinal cord motor neurons. Conclusion: Calpain-mediated MFN2 degradation is a novel mechanism regulating mitochondrial fusion during glutamate excitotoxicity. Significance: MFN2 might be a novel therapeutic target against glutamate excitotoxicity in motor neurons.Mitochondrial dysfunction plays a central role in glutamate-evoked neuronal excitotoxicity, and mitochondrial fission/fusion dynamics are essential for mitochondrial morphology and function. Here, we establish a novel mechanistic linker among glutamate excitotoxicity, mitochondrial dynamics, and mitochondrial dysfunction in spinal cord motor neurons. Ca2+-dependent activation of the cysteine protease calpain in response to glutamate results in the degradation of a key mitochondrial outer membrane fusion regulator, mitofusin 2 (MFN2), and leads to MFN2-mediated mitochondrial fragmentation preceding glutamate-induced neuronal death. MFN2 deficiency impairs mitochondrial function, induces motor neuronal death, and renders motor neurons vulnerable to glutamate excitotoxicity. Conversely, MFN2 overexpression blocks glutamate-induced mitochondrial fragmentation, mitochondrial dysfunction, and/or neuronal death in spinal cord motor neurons both in vitro and in mice. The inhibition of calpain activation also alleviates glutamate-induced excitotoxicity of mitochondria and neurons. Overall, these results suggest that glutamate excitotoxicity causes mitochondrial dysfunction by impairing mitochondrial dynamics via calpain-mediated MFN2 degradation in motor neurons and thus present a molecular mechanism coupling glutamate excitotoxicity and mitochondrial dysfunction.