ArticleThe Journal of biological chemistry2008
A disease-causing point mutation in human mitochondrial tRNAMet rsults in tRNA misfolding leading to defects in translational initiation and elongation.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 33 citations in OpenAlex.
- Diverse mitogenomic variations contribute to population differentiation in Eurasian tree sparrows (Zoological research · 2026Article
- Selection of initiator tRNA and start codon by mammalian mitochondrial initiation factor 3 in leaderless mRNA translation.Nucleic acids research · 2025Article
- Adenine Methylation Enhances the Conformational Flexibility of an RNA Hairpin Tetraloop.The journal of physical chemistry. B · 2024Article
- Review
- Genome-wide analysis of theProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Structural basis for impaired 5' processing of a mutant tRNA associated with defects in neuronal homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Single-nucleotide control of tRNA folding cooperativity under near-cellular conditions.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Structure and Dynamics of tRNAACS omega · 2018Article
- tRNA Modifications: Impact on Structure and Thermal Adaptation.Biomolecules · 2017Review
- Inhibiting translation elongation can aid genome duplication in Escherichia coli.Nucleic acids research · 2017Article
- A deafness-associated tRNAAsp mutation alters the m1G37 modification, aminoacylation and stability of tRNAAsp and mitochondrial function.Nucleic acids research · 2016Article
- RNA modification enzyme TruB is a tRNA chaperone.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Emerging roles of tRNA in adaptive translation, signalling dynamics and disease.Nature reviews. Genetics · 2015Review
- Native tertiary structure and nucleoside modifications suppress tRNA's intrinsic ability to activate the innate immune sensor PKR.PloS one · 2013Article
- The human mitochondrial tRNAMet: structure/function relationship of a unique modification in the decoding of unconventional codons.Journal of molecular biology · 2011Article
- A cytidine deaminase edits C to U in transfer RNAs in Archaea.Science (New York, N.Y.) · 2009Article
- The Importance of Being Modified: The Role of RNA Modifications in Translational Fidelity.The EnzymesReview
- Mechanism of protein biosynthesis in mammalian mitochondria.Biochimica et biophysica actaReview
- Analysis of the functional consequences of lethal mutations in mitochondrial translational elongation factors.Biochimica et biophysica actaArticle
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The mitochondrial tRNA genes are hot spots for mutations that lead to human disease. A single point mutation (T4409C) in the gene for human mitochondrial tRNA(Met) (hmtRNA(Met)) has been found to cause mitochondrial myopathy. This mutation results in the replacement of U8 in hmtRNA(Met) with a C8. The hmtRNA(Met) serves both in translational initiation and elongation in human mitochondria making this tRNA of particular interest in mitochondrial protein synthesis. Here we show that the single 8U-->C mutation leads to a failure of the tRNA to respond conformationally to Mg(2+). This mutation results in a drastic disruption of the structure of the hmtRNA(Met), which significantly reduces its aminoacylation. The small fraction of hmtRNA(Met) that can be aminoacylated is not formylated by the mitochondrial Met-tRNA transformylase preventing its function in initiation, and it is unable to form a stable ternary complex with elongation factor EF-Tu preventing any participation in chain elongation. We have used structural probing and molecular reconstitution experiments to examine the structures formed by the normal and mutated tRNAs. In the presence of Mg(2+), the normal tRNA displays the structural features expected of a tRNA. However, even in the presence of Mg(2+), the mutated tRNA does not form the cloverleaf structure typical of tRNAs. Thus, we believe that this mutation has disrupted a critical Mg(2+)-binding site on the tRNA required for formation of the biologically active structure. This work establishes a foundation for understanding the physiological consequences of the numerous mitochondrial tRNA mutations that result in disease in humans.
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