IDENTIFICATION AND CHARACTERIZATION OF NUCLEAR GENES RESPONSIBLE FOR HUMAN MITOCHONDRIAL DISORDERS

Albeit still insufficiently acknowledged, mitochondrial disease encompasses a substantial fraction of human inherited disorders. The inclusive term "mitochondrial medicine" has recently been coined to account for the broad functional implications of mitochondria in normal and disease conditions. Mitochondrial disorders are very heterogeneous, can affect any organ, at any age, and responsible genes are still missing in most cases. These features make the diagnosis of mitochondrial disease difficult, and in many instances cause these disorders to be overlooked. Effective therapy is missing as well. Nevertheless, great progress has been made in this field in the past decade, thanks to the discovery of new genes relevant to disease, and the investigation of the physiopathology of these disorders through a multidisciplinary approach. In recent years we have been finding several new disease genes, which are responsible for well-defined mitochondrial syndromes. However, the function of these genes is still completely or largely unknown. Using in vitro biochemical and molecular approaches, we shall carry out the characterization of the proteins encoded by these genes. At the same time, we shall also create a series of disease models, from unicellular, user friendly systems, such as cultured mammalian cells and baker's yeast recombinant strains, to mutant animals of increasing complexity and similarity to humans, namely the fruit fly (D. melanogaster) and the house mouse (Mus musculus). The study of these models will help us understand the physiopathology of the disorders caused by the defective genes, gain insight on their function and related metabolic pathways, and devise sensible and specific therapeutic strategies.