PubMed · 16143865
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Friedrich C Luft. 2005. How complex is Complex I?. https://doi.org/10.1007/s00109-005-0708-7
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The contribution of mitochondria to the manifestation of disease is ascribed largely to the production of reactive oxygen species (ROS), which are obligatory by-products of aerobiosis. Studies using isolated mitochondria have revealed multiple potential sites and circumstances of ROS production but the relevance of these to in situ conditions is limited. In this article, we focus on bioenergetic factors that promote ROS generation at physiologically relevant sites in mitochondria. Emphasis is given to ROS generation by complex I--the first component of the respiratory chain--and to how the NADH:NAD+ ratio regulates ROS formation. Complex I is a physiologically and pathologically relevant ROS-forming site that is important not only in normal mitochondrial energy production but also in the pathogenesis of Parkinson's disease, which is the second most common neurodegenerative disease.
Complex I of Escherichia coli is encoded by 13 consecutive genes, called the nuo operon. A chromosomal deletion of all nuo genes has been achieved by homologous recombination. A vector that encodes all of the nuo genes has been constructed, and it expresses a functional enzyme.
Proton pumping respiratory complex I (NADH:ubiquinone oxidoreductase) is a major component of the oxidative phosphorylation system in mitochondria and many bacteria. In mammalian cells it provides 40% of the proton motive force needed to make ATP. Defects in this giant and most complicated membrane-bound enzyme cause numerous human disorders. Yet the mechanism of complex I is still elusive. A group exhibiting redox-linked protonation that is associated with iron-sulfur cluster N2 of complex I has been proposed to act as a central component of the proton pumping machinery. Here we show that a histidine in the 49-kDa subunit that resides near iron-sulfur cluster N2 confers this redox-Bohr effect. Mutating this residue to methionine in complex I from Yarrowia lipolytica resulted in a marked shift of the redox midpoint potential of iron-sulfur cluster N2 to the negative and abolished the redox-Bohr effect. However, the mutation did not significantly affect the catalytic activity of complex I and protons were pumped with an unchanged stoichiometry of 4 H(+)/2e(-). This finding has significant implications on the discussion about possible proton pumping mechanism for complex I.