Mitochondrial -Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species

We suggested that mitochondrial matrix dehydrogenases other than complex I can contribute to the observed reactive oxygen species production in the absence of inhibitors of the mitochondrial respiratory chain

A. A. Starkov

2004

Scholarcy highlights

  • Reactive oxygen species are thought to contribute to neuronal cell death caused by ischemia, excitotoxicity, and various acute and chronic neurological disorders
  • A novel fluorescent probe for H2O2, Amplex Red, has become available that is suitable for measurements with isolated mitochondria
  • We have determined that it is sufficiently sensitive and its fluorescent response is linearly related to H2O2 even at levels that are generated by mitochondria in the absence of respiratory chain inhibitors
  • The interpretation dihydrolipoyl dehydrogenase ϩ/Ϫ mice compared with their littermate controls. of such experiments may be complicated because the source of reactive oxygen species could be anything that is in a redox equilibrium with intramitochondrial NADPH
  • Considering that KGDHC-mediated ROS production finding that H2O2 production is frequently reported as being requires a fully active complex with all the cofactors and subalmost absent in the presence of succinate and rotenone, the fact that the enzyme activity is stimulated by Ca 2ϩ and ADP may perhaps account for previous findings that mitochondrial ROS production was increased by Ca 2ϩ, Ca 2ϩ in the presence of rotenone and succinate, and by ADP
  • Maximum respiration rates were reduced only when ␣-ketoglutarate was oxidized; there was no significant difference in maximum respiration rates or respira
  • The results presented here challenge the idea of a single “major” site of ROS production in mitochondria, whether it be complexes I, II, and III or the Dld component, and emphasize the necessity of additional systematic research on the mechanisms and regulation of mitochondrial ROS production
  • This hypothesis is strongly supported by the results presented in the accompanying report by Tretter and Adam-Vizi that demonstrated that reactive oxygen species production by isolated KGDHC is strongly dependent on the NADH/NAD ϩ ratio

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