Journal
RNA
Volume 14, Issue 11, Pages 2407-2416Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.1208808
Keywords
mitochondria; mtDNA; tRNA; suppression; A3243G mutation; tRNA synthetase
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Funding
- National Institutes of Health
- Muscular Dystrophy Association
- American Diabetes Association
- Juvenile Diabetes Foundation International
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The A3243G mutation in the human mitochondrial tRNA(Leu(UUR)) gene causes a number of human diseases. This mutation reduces the level and fraction of aminoacylated tRNA(Leu(UUR)) and eliminates nucleotide modification at the wobble position of the anticodon. These deficiencies are associated with mitochondrial translation defects that result in decreased levels of mitochondrial translation products and respiratory chain enzyme activities. We have suppressed the respiratory chain defects in A3243G mutant cells by overexpressing human mitochondrial leucyl-tRNA synthetase. The rates of oxygen consumption in suppressed cells were directly proportional to the levels of leucyl-tRNA synthetase. Fifteenfold higher levels of leucyl-tRNA synthetase resulted in wild-type respiratory chain function. The suppressed cells had increased steady-state levels of tRNA Leu(UUR) and up to threefold higher steady-state levels of mitochondrial translation products, but did not have rates of protein synthesis above those in parental mutant cells. These data suggest that suppression of the A3243G mutation occurred by increasing protein stability. This suppression of a tRNA gene mutation by increasing the steady-state levels of its cognate aminoacyl-tRNA synthetase is a model for potential therapies for human pathogenic tRNA mutations.
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