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 Müller 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 Müller glial cells, was reduced dose-dependently by rotenone with no changes in GLAST expression. Our findings suggest that complex I-derived free radicals and disruption of glutamate transport might represent key elements for explaining the selective retinal ganglion cell death in LHON.
MeSH terms
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Animals
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Animals, Newborn
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Cell Death / drug effects
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Cell Death / physiology
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Cells, Cultured
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Dose-Response Relationship, Drug
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Electron Transport Complex I / antagonists & inhibitors
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Electron Transport Complex I / metabolism*
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Energy Metabolism / drug effects
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Energy Metabolism / physiology
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Excitatory Amino Acid Transporter 1 / metabolism
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Free Radicals / metabolism
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Glutamic Acid / metabolism*
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Lipid Peroxidation / drug effects
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Lipid Peroxidation / physiology
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Mitochondria / drug effects
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Mitochondria / genetics
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Mitochondria / metabolism*
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Neuroglia / drug effects
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Neuroglia / metabolism
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Neuroglia / pathology
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Optic Atrophy, Hereditary, Leber / genetics
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Optic Atrophy, Hereditary, Leber / metabolism*
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Optic Atrophy, Hereditary, Leber / physiopathology
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Oxidative Stress / drug effects
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Oxidative Stress / physiology*
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Rats
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Rats, Wistar
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Retina / metabolism*
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Retina / pathology
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Retina / physiopathology
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Retinal Ganglion Cells / drug effects
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Retinal Ganglion Cells / metabolism
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Retinal Ganglion Cells / pathology
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Rotenone / toxicity
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Uncoupling Agents / toxicity
Substances
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Excitatory Amino Acid Transporter 1
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Free Radicals
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Uncoupling Agents
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Rotenone
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Glutamic Acid
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Electron Transport Complex I