Grant: Project Grant

All cells in the body require a steady source of chemical energy to carry out their normal physiological functions. The majority of this chemical energy, which is packaged as a compound called ATP, is produced by the oxidation of carbohydrate and fat in a biochemical process called oxidative phosphorylation. This process takes place in a compartment of the cell called the mitochondrion, and is carried out by several large protein complexes that constitute the mitochondrial respiratory chain. Respiratory chain dysfunction interferes with the normal supply of energy, and this produces a wide variety of different diseases, the nature and severity of which depend on the exact genetic defect. The genetics of respiratory chain diseases is complicated by the fact that some components of the system are encoded in nuclear genes, others in a small genome that is contained within the mitochondria themselves. Diseases caused by nuclear gene defects generally produce the most severe phenotypes (neurodegeneration, heart or liver failure) with onset at birth or during early infancy, and are usually fatal. One of the most common clinical presentations of mitochondrial disease in infants is called Leigh Syndrome. This is a severe neurodegenerative disease that nearly always fatal in early life and for which there is no treatment. This proposal is aimed at investigating the mechanism by which a mutation in a gene that codes for a protein that is a member of the family of proteins that normally transport metabolites into mitochondria causes the disease. Characterization of the function of the genes in which we identify mutations provides biological insight into the normal assembly and function of the respiratory chain, and this we hope will ultimately permit us to devise treatments for these devastating disorders.