Understanding the molecular mechanism of complex I and its roles in human disease
Mammalian complex I (NADH:ubiquinone oxidoreductase) is a crucial mitochondrial enzyme. It oxidises NADH from the tricarboxylic acid cycle, fatty-acid oxidation and glycolysis, reduces ubiquinone for the rest of the respiratory chain, and transports protons across the inner mitochondrial membrane to support ATP synthesis. It is also a major contributor to cellular reactive oxygen species production and oxidative stress. With nine redox cofactors and 44 different subunits, encoded on both the nuclear and mitochondrial genomes, mammalian complex I is one of the largest, most complicated enzymes in the cell. We aim to determine the structure of mammalian complex I, and its mechanisms of catalysis and reactive oxygen species production.
Complex I is linked to medicine on many different levels: from mutations in its subunits and assembly factors that cause mitochondrial diseases, through reactive oxygen species production and oxidative damage (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. We aim to build on our knowledge of structure and mechanism to understand human complex I dysfunctions on the molecular level, and to elucidate the role of complex I in genetically, environmentally and pharmacologically-linked mitochondrial dysfunctions.