ROLE OF SHY1p IN THE YEAST MODEL OF LEIGH’S SYNDROME

Leigh’s syndrome (LS) is an infantile dramatic neurological disorder, belonging to the class of mitochondrial diseases. LS is the most frequent among the hundred of mitochondrial diseases, but it’s a rare pathology in the general population. However all the mitochondrial neuromyopathies in humans affect to more than 1 in 10,000 individuals in the United States and Europe. To date, there is no cure for mitochondrial diseases. In the majority of the cases LS is characterized by severe deficiency of the enzyme cytochrome c oxidase (COX). COX is a mitochondrial enzyme necessary for energy production in the cells; it is formed in human by 13 different subunits and contains heme and copper which are necessary for its catalytic activity. According with the complexity of the enzyme, COX assembly is a complicated process that requires, in addition of the structural subunits, the assistance of more than 20 nuclear gene products. In the majority of the cases, LS is associated with mutations in the SURF1 gene that encodes for a protein necessary for an early step of the COX assembly. At the present the exact function of Surf1p is still not known. Recent studies, performed by our group using the yeast Saccharomyces cerevisiae as LS model system, have established that the role of Shy1p/Surfip is related to the maturation of subunit I of COX. Despite their simplicity yeast cells are similar to higher eukaryotes and have been used as an excellent single cell model to understand the biology of more complex eukaryotic organisms and in particular to gain insight into the functional basis of human mitochondrial diseases. The main objective of this project is to disclose the role of Shy1p in the COX assembly process using the yeast model of LS. The understanding of the exact function of Surf1/Shy1 will shed light into the pathogenesis of LS at the molecular level and it is necessary to develop new therapeutical approach to combat the disease.