1. Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON)
- Author
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Beretta, S, Wood, JPM, Derham, B, SALA, GESSICA, TREMOLIZZO, LUCIO, Osborne, NN, FERRARESE, CARLO, Beretta, S, Wood, J, Derham, B, Sala, G, Tremolizzo, L, Ferrarese, C, and Osborne, N
- Subjects
Retinal Ganglion Cells ,Free Radicals ,Glutamic Acid ,Optic Atrophy, Hereditary, Leber ,complex 1 ,GLAST ,Retina ,Rotenone ,Animals ,Rats, Wistar ,Cells, Cultured ,MED/26 - NEUROLOGIA ,Neurons ,reactive oxygen specie ,Electron Transport Complex I ,leber hereditary optic neuropathy (LHON) ,Cell Death ,Dose-Response Relationship, Drug ,Uncoupling Agents ,Mitochondria ,Rats ,Excitatory Amino Acid Transporter 1 ,Oxidative Stress ,Animals, Newborn ,Lipid Peroxidation ,Energy Metabolism ,excitotoxicity ,Neuroglia - Abstract
Leber Hereditary Optic Neuropathy (LHON) is a maternally inherited form of visual loss, due to selective degeneration of retinal ganglion cells. Despite the established aetiological association between LHON and mitochondrial DNA mutations affecting complex I of the electron transport chain, the pathophysiology of this disorder remains obscure. Primary rat retinal cultures were exposed to increasing concentrations of rotenone to titrate complex I inhibition. Neural cells were more sensitive than Mfiller glial cells to rotenone toxicity. Rotenone induced an increase in mitochondrial-derived free radicals and lipid peroxidation. Sodium -dependent glutamate uptake, which is mostly mediated by the glutamate transporter GLAST expressed by Mfiller glial cells, was reduced dose-dependently by rotenone with no changes in GLAST expression. Our findings suggest that complex 1-derived free radicals and disruption of glutamate transport might represent key elements for explaining the selective retinal ganglion cell death in LHON. (c) 2006 Elsevier Inc. All rights reserved.
- Published
- 2005