Overexpressed mitochondrial leucyl-tRNA synthetase suppresses the A3243G mutation in the mitochondrial tRNALeu(UUR) gene
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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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In m.3243A N G cells, overexpression of leucyl synthetase recovers wild-type RC function.
“In mutant m.3243A N G cells, this overexpression was capable of recovering wildtype RC function.”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [166]
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- Authors
- Park, H., Davidson, E., & King, M. P.
- Affiliations
- Thomas Jefferson University (US)
- ORCID
- Davidson, Edgar
- Venue
- RNA
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-09-16
- Volume
- 14
- Issue
- 11
- Pages
- 2407-2416
- ISSN
- 1355-8382 (ISSN-L)
- 1469-9001
- PMC
- PMC2578859
- OpenAlex
- W2137509482
- Cited by
- 58
- References
- 48
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 5 · 2016: 2 · 2015: 6 · 2014: 8 · 2013: 2 · 2012: 4
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- RNA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- American Diabetes Association
- Muscular Dystrophy Association
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- A3243G mutation, aminoacyl-tRNA synthetase, respiratory chain deficiency, mitochondrial translation, protein stability, oxygen consumption
- MeSH terms
- Cell Line, DNA, Mitochondrial, Electron Transport, Humans, Leucine-tRNA Ligase, Mitochondria, Mutation, RNA, Transfer, Amino Acyl, Suppression, Genetic, Protein Biosynthesis, Mitochondrial Diseases
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