MFN2 Couples Glutamate Excitotoxicity and Mitochondrial Dysfunction in Motor Neurons*

• DOI: 10.1074/jbc.m114.617167
• Publication Date: 2014-11-22T05:44:56Z
• Authors: Wenzhang Wang; Fan Zhang; Li Li; Fangqiang Tang; Sandra L. Siedlak; Hisashi Fujioka; Yingchao Liu; Bo Su; Yan Pi; Xinglong Wang
• Keywords: Male; Motor Neurons; 0303 health sciences; Cell Death; Calpain; Primary Cell Culture; Glutamic Acid; Membrane Proteins; Mice, Transgenic; Embryo, Mammalian; Mitochondrial Dynamics; GTP Phosphohydrolases; Mitochondria; Rats; Mitochondrial Proteins; Mice; 03 medical and health sciences; Gene Expression Regulation; Proteolysis; Animals; Calcium; Female

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. Ca(2+)-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.