Inhibitors of the Quinone-binding Site Allow Rapid Superoxide Production from Mitochondrial NADH:Ubiquinone Oxidoreductase (Complex I)

We examined the rates of superoxide generation by rat skeletal muscle mitochondria under a variety of conditions

Adrian J. Lambert

2004

Scholarcy highlights

  • Removed from the cytosol, as in the case of copper/zinc superoxide dismutase nullizygous mice, the effects are not lethal, an increase in sensitivity to oxidative stress is apparent
  • The rate of superoxide production by complex I during NADH-linked forward electron transport was less than 10% of that during succinate-linked reverse electron transport even when complex I was fully reduced by pyruvate plus malate in the presence of the complex III inhibitor, stigmatellin
  • When inhibitors of the quinone-binding site of complex I were added in the presence of ATP to generate a pH gradient, there was a rapid rate of superoxide production by forward electron transport that was as great as the rate seen with reverse electron transport at the same pH gradient
  • In agreement with previous studies, we show that superoxide production by complex I during reverse electron transport is huge compared with forward electron transport under similar conditions
  • Port at the high rates seen during reverse electron transport in intact mitochondria, and which site in complex I generates the majority of the superoxide?
  • Conditions of High Rates of Superoxide Production by Compex I—In terms of conditions, first, we demonstrate that a pH gradient across the mitochondrial inner membrane during forward or reverse electron transfer is required for high rates of superoxide production
  • During forward electron transport, complex I produces superoxide at very low rates in its native state, but the rate can increase 10 –30-fold in the presence of Q site inhibitors

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