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Author Notes:

Corresponding author. Mailing address: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. Phone: (513) 636-3337. Fax: (513) 636-2261. E-mail: min-xin.guan@cchmc.org

This paper is dedicated to the memory of Giuseppe Attardi, a pioneer in mitochondrial genetics and biomedicine.

We are grateful to Anne Chomyn (California Institute of Technology) for cell lines and Linda Spremulli (University of North Carolina) for the human LARS2 cDNA plasmid.


Research Funding:

This work was supported by Public Health Service grants RO1NS44015 from the National Institute of Neurological Disorders and Stroke and RO1DC05230 and RO1DC07696 from the National Institute on Deafness and Other Communication Disorders to M.X.G.

Human Mitochondrial Leucyl-tRNA Synthetase Corrects Mitochondrial Dysfunctions Due to the tRNALeu(UUR) A3243G Mutation, Associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Symptoms and Diabetes


Journal Title:

Molecular and Cellular Biology


Volume 30, Number 9


, Pages 2147-2154

Type of Work:

Article | Final Publisher PDF


Mutations in mitochondrial tRNA genes are associated with a wide spectrum of human diseases. In particular, the tRNALeu(UUR) A3243G mutation causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS) and 2% of cases of type 2 diabetes. The primary defect in this mutation was an inefficient aminoacylation of the tRNALeu(UUR). In the present study, we have investigated the molecular mechanism of the A3243G mutation and whether the overexpression of human mitochondrial leucyl-tRNA synthetase (LARS2) in the cytoplasmic hybrid (cybrid) cells carrying the A3243G mutation corrects the mitochondrial dysfunctions. Human LARS2 localizes exclusively to mitochondria, and LARS2 is expressed ubiquitously but most abundantly in tissues with high metabolic rates. We showed that the alteration of aminoacylation tRNALeu(UUR) caused by the A3243G mutation led to mitochondrial translational defects and thereby reduced the aminoacylated efficiencies of tRNALeu(UUR) as well as tRNAAla and tRNAMet. We demonstrated that the transfer of human mitochondrial leucyl-tRNA synthetase into the cybrid cells carrying the A3243G mutation improved the efficiency of aminoacylation and stability of mitochondrial tRNAs and then increased the rates of mitochondrial translation and respiration, consequently correcting the mitochondrial dysfunction. These findings provide new insights into the molecular mechanism of maternally inherited diseases and a step toward therapeutic interventions for these disorders.

Copyright information:

© 2010, American Society for Microbiology

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