Title |
The isolated carboxy‐terminal domain of human mitochondrial leucyl‐tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells
|
---|---|
Published in |
EMBO Molecular Medicine, January 2014
|
DOI | 10.1002/emmm.201303198 |
Pubmed ID | |
Authors |
Elena Perli, Carla Giordano, Annalinda Pisano, Arianna Montanari, Antonio F Campese, Aurelio Reyes, Daniele Ghezzi, Alessia Nasca, Helen A Tuppen, Maurizia Orlandi, Patrizio Di Micco, Elena Poser, Robert W Taylor, Gianni Colotti, Silvia Francisci, Veronica Morea, Laura Frontali, Massimo Zeviani, Giulia d'Amati |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Brazil | 1 | 2% |
Unknown | 50 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 15 | 29% |
Student > Ph. D. Student | 9 | 18% |
Student > Master | 6 | 12% |
Professor > Associate Professor | 4 | 8% |
Student > Bachelor | 3 | 6% |
Other | 7 | 14% |
Unknown | 7 | 14% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 14 | 27% |
Biochemistry, Genetics and Molecular Biology | 13 | 25% |
Medicine and Dentistry | 6 | 12% |
Neuroscience | 4 | 8% |
Chemistry | 2 | 4% |
Other | 1 | 2% |
Unknown | 11 | 22% |