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

@article{Lambert2004InhibitorsOT,
  title={Inhibitors of the Quinone-binding Site Allow Rapid Superoxide Production from Mitochondrial NADH:Ubiquinone Oxidoreductase (Complex I)*},
  author={Adrian J Lambert and Martin D. Brand},
  journal={Journal of Biological Chemistry},
  year={2004},
  volume={279},
  pages={39414 - 39420}
}
Neither the route of electron transport nor the sites or mechanism of superoxide production in mitochondrial complex I has been established. We examined the rates of superoxide generation (measured as hydrogen peroxide production) by rat skeletal muscle mitochondria under a variety of conditions. 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… Expand
Evidence for Two Sites of Superoxide Production by Mitochondrial NADH-Ubiquinone Oxidoreductase (Complex I)*
TLDR
A two-site model of complex I superoxide production is supported; one site in equilibrium with the NAD pool, presumably the flavin of the FMN moiety and the other dependent not only on NAD redox state, but also on protonmotive force and the reduction state of the Q pool. Expand
A Possible Site of Superoxide Generation in the Complex I Segment of Rat Heart Mitochondria
TLDR
The results suggest that the major site of superoxide generation is not flavin, but protein-associated ubisemiquinones which are spin-coupled with iron-sulfer cluster N2. Expand
The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria
  • L. Kussmaul, J. Hirst
  • Chemistry, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 2006
TLDR
The mechanism for the isolated enzyme isolated from bovine heart mitochondria is linked to studies on intact mitochondria, in which superoxide production is enhanced when the NAD+ pool is reduced, and forms a foundation for formulating causative connections between complex I defects and pathological effects. Expand
Superoxide Is Produced by the Reduced Flavin in Mitochondrial Complex I
TLDR
The unified mechanism describes how reactive oxygen species production by complex I responds to changes in cellular conditions and establishes a route to understanding causative connections between the enzyme and its pathological effects and to developing rational strategies for addressing them. Expand
Localization of superoxide anion production to mitochondrial electron transport chain in 3-NPA-treated cells.
TLDR
3-NPA increased O2- generation in mitochondria respiring on the complex I substrates pyruvate+malate, an effect fully inhibited by rotenone, and results indicate that in the presence of 3- NPA, mitochondria generate O2 - from a site between the ubiquinol pool and the 3-Npa block in the respiratory complex II. Expand
Production of reactive oxygen species by complex I (NADH:ubiquinone oxidoreductase) from Escherichia coli and comparison to the enzyme from mitochondria.
TLDR
The results confirm previous proposals that O2 reacts with the fully reduced flavin mononucleotide and are consistent with (but do not prove) a specific role for cluster N1a in determining the outcome of O2 reduction; possible reaction mechanisms are discussed. Expand
The 2-Oxoacid Dehydrogenase Complexes in Mitochondria Can Produce Superoxide/Hydrogen Peroxide at Much Higher Rates Than Complex I*
TLDR
The observed rates of H2O2 production over a range of different NAD(P)H reduction levels in isolated skeletal muscle mitochondria under conditions that favored superoxide/H2 O2 production from complex I, the OG DH complex, the BCKDH complex, or the PDH complex were compared. Expand
Superoxide Radical Formation by Pure Complex I (NADH:Ubiquinone Oxidoreductase) from Yarrowia lipolytica*
TLDR
It is shown that isolated complex I from Yarrowia lipolytica forms superoxide at a rate of 0.15% of the rate measured for catalytic turnover, and that oxygen accepts electrons from FMNH or FMN semiquinone either directly or via more hydrophilic ubiquinone derivatives. Expand
Mitochondrial Complex I superoxide production is attenuated by uncoupling.
TLDR
The data suggest that Complex I mitochondrial superoxide production can be attenuated by uncoupling, which means by acceleration of Complex I H(+) pumping due to the respiratory control, but when this acceleration is prevented by 5-(N-ethyl-N-isopropyl) amiloride inhibition, no attenuation ofsuperoxide production takes place. Expand
High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates.
TLDR
The present results indicate that reverse-electron transfer-mediated superoxide production can occur under physiologically realistic substrate conditions and suggest that oxaloacetate inhibition of complex II may be an adaptive mechanism to minimize this. Expand
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The site of production of superoxide radical in mitochondrial Complex I is not a bound ubisemiquinone but presumably iron–sulfur cluster N2
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