Journal
EMBO MOLECULAR MEDICINE
Volume 6, Issue 2, Pages 169-182Publisher
WILEY
DOI: 10.1002/emmm.201303198
Keywords
aminoacyl-tRNA synthetases; mitochondrial disease; mitochondrial tRNA mutations; molecular therapy
Categories
Funding
- Istituto Pasteur-Fondazione Cenci Bolognetti
- Telethon-Italy [GGP13097]
- Associazione Talarico per i giovani nel mondo
- Pasteur Institute-Cenci Bolognetti Foundation
- Sapienza, University of Rome
- Wellcome Trust [096919/Z/11/Z]
- MRC [MC_UP_1002/1, MR/K000608/1] Funding Source: UKRI
- Medical Research Council [MR/K000608/1, MC_UP_1002/1] Funding Source: researchfish
Ask authors/readers for more resources
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(Leu(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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available