A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics

6533b7d7fe1ef96bd1268692

RESEARCH PRODUCT

A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics

Bernd Wissinger You Hyun Noh Marcel V. Alavi Terry S. Kang Won-kyu Ju Mark H. Ellisman Robert N. Weinreb Keunyoung Kim James D. Lindsey Guy Perkins Ray T. Scott Duy Nguyen

subject

Retinal Ganglion Cells Cancer Research Receptor expression Excitotoxicity Apoptosis Neurodegenerative Mitochondrion Eye medicine.disease_cause GTP Phosphohydrolases Mice 0302 clinical medicine Receptors oxidative stress Phosphorylation bcl-2-Associated X Protein 0303 health sciences biology Glutamate receptor Mitochondria Up-Regulation Cell biology mitochondrial fusion Autosomal Dominant Original Article bcl-Associated Death Protein Mitochondrial fission N-Methyl-D-Aspartate Biotechnology mitochondrial fragmentation Oncology and Carcinogenesis Immunology bcl-X Protein SOD2 Glutamic Acid Receptors N-Methyl-D-Aspartate NMDA receptors Cell Line 03 medical and health sciences Cellular and Molecular Neuroscience Bcl-2-associated X protein Optic Atrophy Autosomal Dominant medicine Animals Eye Disease and Disorders of Vision 030304 developmental biology Superoxide Dismutase Neurosciences Cell Biology Molecular biology eye diseases Oxidative Stress Optic Atrophy Mutation biology.protein OPA1 mutation Biochemistry and Cell Biology sense organs glutamate excitotoxicity 030217 neurology & neurosurgery

description

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. Opa1enu/+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 Opa1enu/+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. © 2011 Macmillan Publishers Limited. All rights reserved.

year	journal	country	edition	language
2011-12-01	Cell Death & Disease

https://doi.org/10.1038/cddis.2011.117