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

D Nguyen,Y H Noh,R T Scott,K-Y Kim,T Kang,J D Lindsey,G A Perkins,M H Ellisman,M V Alavi,B Wissinger,W-K Ju,R N Weinreb

doi:10.1038/cddis.2011.117

D Nguyen, Y H Noh + Show 10 more

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

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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. 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.

Highlights

MtDNA stability, maintenance of mitochondrial electron transport, scavenger of reactive oxygen species, mitochondrial coupling, apoptotic signaling, and mitochondrial cristae remodeling.[9,10] There is only unanimous agreement that optic atrophy type 1 (OPA1) is necessary for mitochondrial fusion, because from yeast, to worm, to fly, to man, all studies describe fragmented mitochondrial networks upon loss of OPA1 function.[11]
retinal ganglion cells (RGCs) loss is accompanied by activation of both astroglia and microglia as indicated by significantly increased glial fibrillary acidic protein (GFAP) expression in the retinas of Opa1enu/ þ mice (Figure 2)
The number of mitochondria, normalized to the total area occupied by axons in each image, was significantly increased in the optic nerve head (ONH) axons of Opa1enu/ þ mice compared with wild-type controls (Figure 3i). These results conclusively show that mutations in the murine OPA1 gene results in increased mitochondrial fission in ONH axons of Opa1enu/ þ mice likely contributing to RGC loss

Summary

Introduction

MtDNA stability, maintenance of mitochondrial electron transport, scavenger of reactive oxygen species, mitochondrial coupling, apoptotic signaling, and mitochondrial cristae remodeling.[9,10] There is only unanimous agreement that OPA1 is necessary for mitochondrial fusion, because from yeast, to worm, to fly, to man, all studies describe fragmented mitochondrial networks upon loss of OPA1 function.[11]. We report that mutations in OPA1 in turn lead to the upregulation of NMDA glutamate receptors as well as the downregulation of mitochondrial SOD2 in the retina of heterozygous Opa1enu/ þ mice. These findings indicate that glutamate excitotoxicity influences the mitochondrial fission/fusion balance (as suggested before), and that altered mitochondrial fusion affects glutamate excitotoxicity. We suggest a new vicious cycle involved in neurodegeneration that includes glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics

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