MFN2 Couples Glutamate Excitotoxicity and Mitochondrial Dysfunction in Motor Neurons

• Published in: The Journal of biological chemistry 2015-01, Vol.290 (1), p.168-182
• Main Authors: Wang, Wenzhang, Zhang, Fan, Li, Li, Tang, Fangqiang, Siedlak, Sandra L., Fujioka, Hisashi, Liu, Yingchao, Su, Bo, Pi, Yan, Wang, Xinglong
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium - pharmacology; Calpain; Calpain - genetics; Calpain - metabolism; Cell Death - drug effects; Embryo, Mammalian; Excitotoxicity; Female; Gene Expression Regulation; Glutamate; Glutamate Excitotoxicity; Glutamic Acid - metabolism; Glutamic Acid - pharmacology; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; MFN2; Mice; Mice, Transgenic; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial Dynamics; Mitochondrial Dynamics - drug effects; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Motor Neuron; Motor Neurons - drug effects; Motor Neurons - metabolism; Motor Neurons - pathology; Neurobiology; Neurodegeneration; Primary Cell Culture; Proteolysis; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - pathology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.617167

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.Mitochondrial function is dependent on mitochondrial fission and fusion dynamics. Calpain-mediated degradation of MFN2 is responsible for glutamate-induced mitochondrial dysfunction and neuronal death in spinal cord motor neurons. Calpain-mediated MFN2 degradation is a novel mechanism regulating mitochondrial fusion during glutamate excitotoxicity. MFN2 might be a novel therapeutic target against glutamate excitotoxicity in motor neurons.