Ulrich Brandt, theme Mitochondrial diseases received a NWO Top grant of € 780,000 for a project entitled: Molecular mechanism and regulation of energy conversion by mitochondrial complex I.
The complexes of oxidative phosphorylation are the major energy converters of aerobic cells that are also involved in multiple other cellular processes. Complex I (NADH:ubiquinone oxidoreductase) is the largest and most complicated respiratory chain enzyme. It is a major source of reactive oxygen species and in man prominently involved in inherited mitochondrial diseases, neurodegenerative disorders and aging. Despite its tremendous biomedical importance, there is large gap of knowledge, when it comes to the mechanism and regulation of mitochondrial complex I. The recently solved bacterial and mitochondrial X-ray structures launch a new phase in complex I research by finally providing the blueprints of this fascinating molecular machine that were desperately needed to unravel its intricate molecular mechanism. Our X-ray structure of mitochondrial complex I and our structure/function studies provided fundamental insights into the design and dynamics of the ubiquinone-binding pocket. It led us to propose an integrated mechanistic model for catalysis and regulation of complex I. Using this hypothesis as a starting point, we will elucidate the still enigmatic molecular mechanism of complex I and its poorly understood regulation by the so-called active/deactive (A/D) transition. Specifically we aim at defining the catalytic and regulatory sub-states of complex I and how they control the chemistry of ubiquinone intermediates by a combination of advanced, mutagenesis based structure/function analysis and structural analysis.
Specifically, we will work out in detail the “mechanics” of the conformational changes by which the charge induced reorganiza¬tion of the ubiquinone binding site leads to the generation of the power stroke transmitted into the membrane arm to drive proton pumping. To this end, we will probe the loop rearrangements within the ubiquinone binding pocket to decipher their workings during catalytic turnover and the A/D transition. Furthermore, we will define the structural features controlling the chemistry of ubiquinone in the different functional states of mitochondrial complex I. Finally, we aim at understanding, how the mechanism of energy conversion of complex I is controlled by the A/D transition at the molecular level.
We expect that at the end of the funding period we can present a refined and experimentally well supported molecular mechanism of energy conversion that integrates the different func¬tional modes of mitochondrial complex I. Although the focus of the proposed study is exclusively on fundamental research, the results will have broad biomedical impact, since complex I dysfunction has been implicated in numerous human pathologies, including inherited mitochondrial disease, M. Parkinson, M. Alzheimer, ischemia/ reperfusion injuries and biological ageing.
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