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

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

EMBO Mol Med 2014 02 10;6(2):169-82. Epub 2014 Jan 10.

Department of Radiology, Oncology and Pathology, Sapienza University of Rome, Rome, Italy.

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.

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http://dx.doi.org/10.1002/emmm.201303198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927953PMC
February 2014

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