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MFN2 couples glutamate excitotoxicity and mitochondrial dysfunction in motor neurons.

Authors: Wang, Wenzhang  Zhang, Fan  Li, Li  Tang, Fangqiang  Siedlak, Sandra L  Fujioka, Hisashi  Liu, Yingchao  Su, Bo  Pi, Yan  Wang, Xinglong 
Citation: Wang W, etal., J Biol Chem. 2015 Jan 2;290(1):168-82. doi: 10.1074/jbc.M114.617167. Epub 2014 Nov 21.
Pubmed: (View Article at PubMed) PMID:25416777
DOI: Full-text: 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. 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.


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CRRD Object Information
CRRD ID: 13204765
Created: 2017-07-18
Species: All species
Last Modified: 2017-07-18
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.