Mfn2 Couples Glutamate Excitotoxicity and Mitochondrial Dysfunction in Motor Neurons [Cell Biology]

November 21st, 2014 by Wang, W., Zhang, F., Li, L., Tang, F., Siedlak, S. L., Fujioka, H., Liu, Y., Su, B., Pi, Y., Wang, X.

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 well 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.