Project Funding Details

Complex I (NADH:ubiquinone oxidoreductase) is crucial for respiration in many aerobic organisms. In mitochondria, it oxidizes NADH from the tricarboxylic acid cycle and ?-oxidation, reduces ubiquinone, and transports protons across the inner membrane, contributing to the proton-motive force that powers ATP synthesis. It is also a major contributor to cellular production of reactive oxygen species (ROS). Complex I is linked to medicine on many different levels: from mutations in its subunits and assembly factors that cause mitochondrial diseases, through the production of reactive oxygen species and oxidative damage (which may be relevant to neurodegenerative diseases such as Parkinson?s disease), to complex I as a potential drug target in diabetes, ischaemia-reperfusion and cancer, and complex I-linked drug side effects. Understanding the functions and dysfunctions of complex I in these contexts is an intellectual and scientific challenge for both medical and basic scientists that must be tackled on multiple levels. Basic molecular knowledge of the enzyme?s structure and mechanism is required to provide a foundation for biomedical function-dysfunction studies of complex I in mitochondrial and cellular systems of greater complexity. The central thrust of the future work of the Mitochondrial Complex I group is to develop and apply structural and mechanistic knowledge about complex I, in order to answer questions about its role in genetically, environmentally and pharmacologically-linked mitochondrial dysfunctions. Thus, we are working toward a high resolution structure of the enyzme, developing model systems for the study of mutations in order to determine the enzyme mechanism and define the molecular-level reasons for genetic complex I dysfunctions, and working with material from rodent model systems and cultured cells to study complex I-related pathologies directly in mammalian cells. On multiple levels these studies also allow complex I-drug interactions to be evaluated as pharmocological mechanisms and the causes of side effects.