title: A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics.
abstract: Glutamate excitotoxicity leads to fragmented mitochondria in neurodegenerative diseases, mediated by nitric oxide and S-nitrosylation of dynamin-related protein 1, a mitochondrial outer membrane fission protein. Optic atrophy gene 1 (OPA1) is an inner membrane protein important for mitochondrial fusion. Autosomal dominant optic atrophy (ADOA), caused by mutations in OPA1, is a neurodegenerative disease affecting mainly retinal ganglion cells (RGCs). Here, we showed that OPA1 deficiency in an ADOA model influences N-methyl-D-aspartate (NMDA) receptor expression, which is involved in glutamate excitotoxicity and oxidative stress. Opa1(enu/+) mice show a slow progressive loss of RGCs, activation of astroglia and microglia, and pronounced mitochondrial fission in optic nerve heads as found by electron tomography. Expression of NMDA receptors (NR1, 2A, and 2B) in the retina of Opa1(enu/+) mice was significantly increased as determined by western blot and immunohistochemistry. Superoxide dismutase 2 (SOD2) expression was significantly decreased, the apoptotic pathway was activated as Bax was increased, and phosphorylated Bad and BcL-xL were decreased. Our results conclusively demonstrate that not only glutamate excitotoxicity and/or oxidative stress alters mitochondrial fission/fusion, but that an imbalance in mitochondrial fission/fusion in turn leads to NMDA receptor upregulation and oxidative stress. Therefore, we propose a new vicious cycle involved in neurodegeneration that includes glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics.
authors.affiliation: The Sophie and Arthur Brody Laboratory for Optic Nerve Biology, Hamilton Glaucoma Center, Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nguyen
authors.forename: M V
authors.initials: MV
authors.lastname: Alavi
authors.forename: K-Y
authors.initials: KY
authors.lastname: Kim
authors.forename: T
authors.initials: T
authors.lastname: Kang
authors.forename: R T
authors.initials: RT
authors.lastname: Scott
authors.forename: Y H
authors.initials: YH
authors.lastname: Noh
authors.forename: J D
authors.initials: JD
authors.lastname: Lindsey
authors.forename: B
authors.initials: B
authors.lastname: Wissinger
authors.forename: M H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: R N
authors.initials: RN
authors.lastname: Weinreb
authors.forename: G A
authors.initials: GA
authors.lastname: Perkins
authors.forename: W-K
authors.initials: WK
authors.lastname: Ju
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D020558:GTP Phosphohydrolases; D018698:Glutamic Acid; D016194:Receptors, N-Methyl-D-Aspartate; D013482:Superoxide Dismutase; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D000099156:Superoxide Dismutase 2; C498809:Opa1 protein, mouse