COPPER CHAPERONES AND CYTOCHROME C OXIDASE DEFICIENCY. FROM PATHOPHYSIOLOGY TO THERAPY

Cytochrome c oxidase (COX) deficiency is a fatal progressive genetic disorder, which causes a severe encephalomyopathy that leads to death in the first years of life. No therapy is currently available for these disease. It is usually due to the fact that one of the genes required for the assembly of COX, an enzyme necessary for cellular respiration, is mutated and does not function properly. Copper is a crucial component of COX and at lest 6 genes are specifically dedicated to its metabolism. We have recently discovered that it is possible to correct the COX defect in cells of patients with mutations in one of these 6 genes, SCO2, by treating cells with copper. Preliminary data about copper supplementation to patients appear promising. Our project aims to characterize the complex relations among the genes involved in copper metabolism and COX. In particular we will characterize two novel human COX assembly genes cloned by our group COX23 and COX19. We study their structure and function, and we will try to understand the mechanism by which copper corrects the COX defect in patient cells. These experiments will help to optimize therapeutic strategies based on copper supplementation, a realistic therapeutic option for the treatment of these otherwise fatal disorders.