ArticleProceedings of the National Academy of Sciences of the United States of America2007
Pathogenic mechanism of a human mitochondrial tRNAPhe mutation associated with myoclonic epilepsy with ragged red fibers syndrome.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 43 citations in OpenAlex.
- Article
- Tissue-specific mitochondrial DNA,Molecular genetics and metabolism reports · 2025Article
- Mitochondrial diseases: from molecular mechanisms to therapeutic advances.Signal transduction and targeted therapy · 2025Review
- Expanding DdCBE-mediated targeting scope to aC motif preference in rat.Molecular therapy. Nucleic acids · 2023Article
- Breaking a single hydrogen bond in the mitochondrial tRNAThe FEBS journal · 2020Article
- Review
- TRMT1-Catalyzed tRNA Modifications Are Required for Redox Homeostasis To Ensure Proper Cellular Proliferation and Oxidative Stress Survival.Molecular and cellular biology · 2017Article
- Mitochondrial transcript maturation and its disorders.Journal of inherited metabolic disease · 2015Review
- tRNA biology in mitochondria.International journal of molecular sciences · 2015Review
- Anticodon G recognition by tRNA synthetases mimics the tRNA core.Trends in biochemical sciences · 2013Article
- Is mitochondrial tRNA(phe) variant m.593T>C a synergistically pathogenic mutation in Chinese LHON families with m.11778G>A?PloS one · 2011Article
- Mechanistic insights into cognate substrate discrimination during proofreading in translation.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- 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.Molecular and cellular biology · 2010Article
- Article
- A disease-causing point mutation in human mitochondrial tRNAMet rsults in tRNA misfolding leading to defects in translational initiation and elongation.The Journal of biological chemistry · 2008Article
- The cost of wobble translation in fungal mitochondrial genomes: integration of two traditional hypotheses.BMC evolutionary biology · 2008Article
- Mechanism of protein biosynthesis in mammalian mitochondria.Biochimica et biophysica actaReview
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Human mitochondrial tRNA (hmt-tRNA) mutations are associated with a variety of diseases including mitochondrial myopathies, diabetes, encephalopathies, and deafness. Because the current understanding of the precise molecular mechanisms of these mutations is limited, there is no efficient method to treat their associated mitochondrial diseases. Here, we use a variety of known mutations in hmt-tRNA(Phe) to investigate the mechanisms that lead to malfunctions. We tested the impact of hmt-tRNA(Phe) mutations on aminoacylation, structure, and translation elongation-factor binding. The majority of the mutants were pleiotropic, exhibiting defects in aminoacylation, global structure, and elongation-factor binding. One notable exception was the G34A anticodon mutation of hmt-tRNA(Phe) (mitochondrial DNA mutation G611A), which is associated with MERRF (myoclonic epilepsy with ragged red fibers). In vitro, the G34A mutation decreases aminoacylation activity by 100-fold, but does not affect global folding or recognition by elongation factor. Furthermore, G34A hmt-tRNA(Phe) does not undergo adenosine-to-inosine (A-to-I) editing, ruling out miscoding as a possible mechanism for mitochondrial malfunction. To improve the aminoacylation state of the mutant tRNA, we modified the tRNA binding domain of the nucleus-encoded human mitochondrial phenylalanyl-tRNA synthetase, which aminoacylates hmt-tRNA(Phe) with cognate phenylalanine. This variant enzyme displayed significantly improved aminoacylation efficiency for the G34A mutant, suggesting a general strategy to treat certain classes of mitochondrial diseases by modification of the corresponding nuclear gene.
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