MODULATION OF ATP SYNTHESIS IN CELLS HARBORING THE ATPASE6 (NARP) MUTATION BY ANTIOXIDANTS.

Among the different groups of inborn errors of metabolism, mitochondrial disorders are the most frequent, with an estimated incidence of at least 1 in 10,000 live births. Mitochondrial disorders usually refer to diseases that are caused by alterations in mitochondrial oxidative phosphorylation (OXPHOS) system, the final biochemical pathway involved in the production of the principal fuel of the cell, ATP. Mitochondria are unique among intracellular structures in that they contain their own DNA (mtDNA). In recent years more than 100 mutations in the mtDNA have been associated with human diseases. One relatively frequent mutation is the T8993G mtDNA ATPase6 gene, which is associated with NARP (Neuropaty, Ataxia, Retinitis Pigmentosa) syndrome. This proposal builds on the preliminary results that we have obtained in a tissue culture model, the cytoplasmic hybrid (cybrids) system, in which NARP patients mitochondria are fused with a tumor cell line lacking mitochondria. We have found that this mutation causes increased reactive oxygen species (ROS) and mitochondrial pH, which worsen mitochondrial dysfunction and that antioxidant agents ameliorate oxidative phosphorylation.We are proposing to extend these studies, to validate them in cells directly derived from patients, and to compare these findings in NARP with other mtDNA mutations.We will try to prove that it is possible to counteract the pathogenic mechanisms leading to oxidative phosphorylation defects and to modulate energy metabolism using antioxidants.