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.
[1]Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA;
[2]Case Western Reserve Univ, Electron Microscopy Core Facil, Cleveland, OH 44106 USA;
[3]Shandong Univ, Dept Neurosurg, Jinan 250012, Peoples R China;
[4]Shandong Univ, Dept Neurobiol, Jinan 250012, Peoples R China;
[5]Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China
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