title: MFN2 couples glutamate excitotoxicity and mitochondrial dysfunction in motor neurons.
abstract: 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.
authors.affiliation: From the Department of Pathology and.
authors.forename: Wenzhang
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the Department of Pathology and the Departments of Neurosurgery and.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: From the Department of Pathology and.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Department of Pathology and.
authors.forename: Fangqiang
authors.initials: F
authors.lastname: Tang
authors.affiliation: From the Department of Pathology and.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.affiliation: Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.affiliation: the Departments of Neurosurgery and.
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Neurobiology, Shandong University, Jinan 250012, China, and.
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.affiliation: the State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Pi
authors.affiliation: From the Department of Pathology and xinglong.wang@case.edu.
authors.forename: Xinglong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002154:Calpain / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004622:Embryo, Mammalian; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018698:Glutamic Acid; D002154:Calpain; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; C489710:Mfn2 protein, rat; D002118:Calcium
keywords: Calpain; Excitotoxicity; Glutamate; Glutamate Excitotoxicity; MFN2; Mitochondria; Mitochondrial Dynamics; Motor Neuron; Neurodegeneration