The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells.

TitleThe isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells.
Publication TypeJournal Article
Year of Publication2014
AuthorsPerli, E, Giordano, C, Pisano, A, Montanari, A, Campese, AF, Reyes, A, Ghezzi, D, Nasca, A, Tuppen, HA, Orlandi, M, Di Micco, P, Poser, E, Taylor, RW, Colotti, G, Francisci, S, Morea, V, Frontali, L, Zeviani, M, d'Amati, G
JournalEMBO Mol Med
Volume6
Issue2
Pagination169-82
Date Published2014 02
ISSN1757-4684
KeywordsAmino Acyl-tRNA Synthetases, Cell Survival, Energy Metabolism, Humans, Mitochondria, Mutation, Peptides, Phenotype, Protein Binding, Protein Structure, Tertiary, Protein Transport, RNA, Transfer, Leu
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.

DOI10.1002/emmm.201303198
Alternate JournalEMBO Mol Med
Citation Key10.1002/emmm.201303198
PubMed ID24413190
PubMed Central IDPMC3927953
Grant ListGGP13097 / / Telethon / Italy
MC_UP_1002/1 / / Medical Research Council / United Kingdom
MR/K000608/1 / / Medical Research Council / United Kingdom
096919/Z/11/Z / / Wellcome Trust / United Kingdom