Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON)

Neurobiol Dis. 2006 Nov;24(2):308-17. doi: 10.1016/j.nbd.2006.07.016. Epub 2006 Sep 7.

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

  • Animals
  • Animals, Newborn
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Electron Transport Complex I / antagonists & inhibitors
  • Electron Transport Complex I / metabolism*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology
  • Excitatory Amino Acid Transporter 1 / metabolism
  • Free Radicals / metabolism
  • Glutamic Acid / metabolism*
  • Lipid Peroxidation / drug effects
  • Lipid Peroxidation / physiology
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Neuroglia / drug effects
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Optic Atrophy, Hereditary, Leber / genetics
  • Optic Atrophy, Hereditary, Leber / metabolism*
  • Optic Atrophy, Hereditary, Leber / physiopathology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Rats
  • Rats, Wistar
  • Retina / metabolism*
  • Retina / pathology
  • Retina / physiopathology
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / pathology
  • Rotenone / toxicity
  • Uncoupling Agents / toxicity

Substances

  • Excitatory Amino Acid Transporter 1
  • Free Radicals
  • Uncoupling Agents
  • Rotenone
  • Glutamic Acid
  • Electron Transport Complex I