Grant: Operating Grant

All cells in the body require chemical energy to carry out their normal physiological functions. The majority of this energy is packaged as a compound called ATP and 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, such as neurodegenerative and heart disease, 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. In fact while there are only 13 proteins coded in the mitochondrial genome, more than 150 nuclear genes are necessary for their synthesis. The mitochondrial genome evolved from a bacterial ancestor, so the manner in which proteins are synthesized in mitochondria resembles that in bacteria; however, many components have been added to the human mitochondrial translational apparatus, and we have a very limited understanding of how the overall process is regulated. Genetic mutations in translation factors cause a wide spectrum of tissue-specific disorders, the basis for which remains an enduring mystery. Our research aims to elucidate the function of the proteins that facilitate translation of the genes encoded in the mitochondrial genome and their role in human disease.