title: Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON).
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.
authors.affiliation: Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Via Cadore 48, 20052 Monza (MI), Italy. simone.beretta@unimib.it
authors.forename: Simone
authors.initials: S
authors.lastname: Beretta
authors.forename: John P M
authors.initials: JP
authors.lastname: Wood
authors.forename: Barry
authors.initials: B
authors.lastname: Derham
authors.forename: Gessica
authors.initials: G
authors.lastname: Sala
authors.forename: Lucio
authors.initials: L
authors.lastname: Tremolizzo
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrarese
authors.forename: Neville N
authors.initials: NN
authors.lastname: Osborne
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012402:Rotenone / Q000633:toxicity; D014475:Uncoupling Agents / Q000633:toxicity
chemical_list: D027341:Excitatory Amino Acid Transporter 1; D005609:Free Radicals; D014475:Uncoupling Agents; D012402:Rotenone; D018698:Glutamic Acid; D042967:Electron Transport Complex I