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.
Beretta, S., Wood, J., Derham, B., Sala, G., Tremolizzo, L., Ferrarese, C., et al. (2006). Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON). NEUROBIOLOGY OF DISEASE, 24(2), 308-317 [10.1016/j.nbd.2006.07.016].
Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON)
Beretta, S;SALA, GESSICA;TREMOLIZZO, LUCIO;FERRARESE, CARLO;
2006
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.
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