title: Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria.
abstract: Mutations in human mitochondrial DNA are often associated with incurable human neuromuscular diseases. Among these mutations, an important number have been identified in tRNA genes, including 29 in the gene MT-TL1 coding for the tRNA(Leu(UUR)). The m.3243A>G mutation was described as the major cause of the MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). This mutation was reported to reduce tRNA(Leu(UUR)) aminoacylation and modification of its anti-codon wobble position, which results in a defective mitochondrial protein synthesis and reduced activities of respiratory chain complexes. In the present study, we have tested whether the mitochondrial targeting of recombinant tRNAs bearing the identity elements for human mitochondrial leucyl-tRNA synthetase can rescue the phenotype caused by MELAS mutation in human transmitochondrial cybrid cells. We demonstrate that nuclear expression and mitochondrial targeting of specifically designed transgenic tRNAs results in an improvement of mitochondrial translation, increased levels of mitochondrial DNA-encoded respiratory complexes subunits, and significant rescue of respiration. These findings prove the possibility to direct tRNAs with changed aminoacylation specificities into mitochondria, thus extending the potential therapeutic strategy of allotopic expression to address mitochondrial disorders.
authors: UMR 7156 University of Strasbourg - CNRS, Molecular Genetics, Genomics & Microbiology, Strasbourg 67084, France.
authors: Olga Z
authors: OZ
authors: Karicheva
authors: Olga A
authors: OA
authors: Kolesnikova
authors: Tom
authors: T
authors: Schirtz
authors: Mikhail Y
authors: MY
authors: Vysokikh
authors: Anne-Marie
authors: AM
authors: Mager-Heckel
authors: Anne
authors: A
authors: Lombès
authors: Abdeldjalil
authors: A
authors: Boucheham
authors: Igor A
authors: IA
authors: Krasheninnikov
authors: Robert P
authors: RP
authors: Martin
authors: Nina
authors: N
authors: Entelis
authors: Ivan
authors: I
authors: Tarassov
mesh_terms: D049148:Aminoacylation; D001483:Base Sequence; D002460:Cell Line; D019069:Cell Respiration; D050259:Genes, Mitochondrial; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D017354:Point Mutation; D014176:Protein Biosynthesis; D034443:RNA Transport; D012356:RNA, Transfer, Leu / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012357:RNA, Transfer, Lys / Q000737:chemistry / Q000378:metabolism
chemical_list: D012356:RNA, Transfer, Leu; D012357:RNA, Transfer, Lys