Grant: Project Grant

All cells in the body require chemical energy to carry out their normal physiological functions. Most 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 way in which proteins are synthesized in mitochondria resembles that in bacteria. The genes coded in the mitochondrial first need to be transcribed by a specific mitochondrial enzyme. As in bacteria they are transcribed as large molecules containing the coding information for all mitochondrial genes. These so-called primary transcripts need to be processed and modified before the proteins they encode can be synthesized, and this in fact the major step at which mitochondrial gene expression is regulated. Many of the genes that have been implicated in mitochondrial disease are involved with the processing and modification of the primary transcripts and subsequent translation of the mature messenger RNAs. The broad goal of our research is to discover exactly how this is regulated and how mutations in the genes involved lead to disease.