Grant: Operating 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. The aim of this proposal is to identify nuclear gene defects in these patients. We will do this by complementing the defect in patient cells by the transfer of normal human chromosomes. This permits us to map the position of the defective gene on a chromosome, and ultimately to identify it. Successful identification of the defective gene leads directly to the development of diagnostic tests that are made freely available to patients and their physicians. Characterization of the function of the genetic mutation provides biological insight into the normal assembly and function of the respiratory chain, which may ultimately permit us to devise treatments for these devastating disorders.