Isolated domains of aminoacyl tRNA syntethases as a novel therapeutic tool for mt tRNA mutation associated disease

Mitochondrial (mt) diseases are neurodegenerative conditions due to mutations in nuclear or mtDNA genes. Among the latter mutations, >50% reside in transfer RNA (tRNA) genes and are responsible for a wide range of syndromes, the most frequent being Mitochondrial Encephalopathy with Lactic Acidosis and Stroke like episodes (MELAS), for which no effective treatment is available at present. tRNAs are small molecules in cells, that carry amino acids to organelles called ribosomes, where they are linked into proteins. Each tRNA is charged with the proper amino acid via a by a family of enzymes called aminoacyl-tRNA synthetases. Based on previous experiments carried out by our group on yeast cells, we hypothesized that short portions of these enzymes can ameliorate the biochemical defects secondary to mutations in mitochondrial tRNA. To verify this hypothesis, we will overexpress these short peptides in human cell lines (transmitochondrial cybrids, engineered to carry only “mutated” mitochondria) to study their effect on mitochondrial bioenergetics. Our preliminary results on this model are encouraging, showing an improvement of mitochondrial function in treated cells.