title: The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells.
abstract: Mitochondrial (mt) diseases are multisystem disorders due to mutations in nuclear or mtDNA genes. Among the latter, more than 50% are located in transfer RNA (tRNA) genes and are responsible for a wide range of syndromes, for which no effective treatment is available at present. We show that three human mt aminoacyl-tRNA syntethases, namely leucyl-, valyl-, and isoleucyl-tRNA synthetase are able to improve both viability and bioenergetic proficiency of human transmitochondrial cybrid cells carrying pathogenic mutations in the mt-tRNA(Ile) gene. Importantly, we further demonstrate that the carboxy-terminal domain of human mt leucyl-tRNA synthetase is both necessary and sufficient to improve the pathologic phenotype associated either with these "mild" mutations or with the "severe" m.3243A>G mutation in the mt-tRNA(L)(eu(UUR)) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNA(Leu(UUR)) with high affinity and stability and, with lower affinity, with mt-tRNA(Ile). Taken together, our results sustain the hypothesis that the carboxy-terminal domain of human mt leucyl-tRNA synthetase can be used to correct mt dysfunctions caused by mt-tRNA mutations.
authors.affiliation: Department of Radiology, Oncology and Pathology, Sapienza University of Rome, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Perli
authors.forename: Carla
authors.initials: C
authors.lastname: Giordano
authors.forename: Annalinda
authors.initials: A
authors.lastname: Pisano
authors.forename: Arianna
authors.initials: A
authors.lastname: Montanari
authors.forename: Antonio F
authors.initials: AF
authors.lastname: Campese
authors.forename: Aurelio
authors.initials: A
authors.lastname: Reyes
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Alessia
authors.initials: A
authors.lastname: Nasca
authors.forename: Helen A
authors.initials: HA
authors.lastname: Tuppen
authors.forename: Maurizia
authors.initials: M
authors.lastname: Orlandi
authors.forename: Patrizio
authors.initials: P
authors.lastname: Di Micco
authors.forename: Elena
authors.initials: E
authors.lastname: Poser
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Gianni
authors.initials: G
authors.lastname: Colotti
authors.forename: Silvia
authors.initials: S
authors.lastname: Francisci
authors.forename: Veronica
authors.initials: V
authors.lastname: Morea
authors.forename: Laura
authors.initials: L
authors.lastname: Frontali
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Giulia
authors.initials: G
authors.lastname: d'Amati
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry* / Q000378:metabolism*; D002470:Cell Survival; D004734:Energy Metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012356:RNA, Transfer, Leu / Q000235:genetics*
chemical_list: D010455:Peptides; D012356:RNA, Transfer, Leu; D000604:Amino Acyl-tRNA Synthetases