ArticleNucleic acids research2021
A deafness-associated tRNA mutation caused pleiotropic effects on the m1G37 modification, processing, stability and aminoacylation of tRNAIle and mitochondrial translation.
Article in Nucleic acids research, 2021. 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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17 citing papers in PubMed, 40 citations in OpenAlex.
- tRNA and tsRNA: From Heterogeneity to Multifaceted Regulators.Biomolecules · 2024Review
- Methylation modifications in tRNA and associated disorders: Current research and potential therapeutic targets.Cell proliferation · 2024Review
- A Novel tsRNA, mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- RNase P: Beyond Precursor tRNA Processing.Genomics, proteomics & bioinformatics · 2024Review
- Maternally inherited non-syndromic hearing loss is linked with a novel mitochondrial ND6 gene mutation.Irish journal of medical science · 2024Article
- Deficient tRNA posttranscription modification dysregulated the mitochondrial quality controls and apoptosis.iScience · 2024Article
- CNature communications · 2024Article
- Screening for Mitochondrial tRNA Variants in 200 Patients with Systemic Lupus Erythematosus.Human heredity · 2024Article
- Research Advances on Deafness Genes Associated with Mitochondrial tRNA-37 Modifications.The journal of international advanced otology · 2023Review
- Induced pluripotent stem cells: ex vivo models for human diseases due to mitochondrial DNA mutations.Journal of biomedical science · 2023Review
- Mitochondrial Cardiomyopathy: The Roles of mt-tRNA Mutations.Journal of clinical medicine · 2022Review
- Novel m.4268T>C mutation in the mitochondrial tRNAWorld journal of clinical cases · 2022Article
- FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism.Nucleic acids research · 2021Article
- Ablation of Mto1 in zebrafish exhibited hypertrophic cardiomyopathy manifested by mitochondrion RNA maturation deficiency.Nucleic acids research · 2021Article
- tRNA Metabolism and Lung Cancer: Beyond Translation.Frontiers in molecular biosciences · 2021Review
- Autophagy: A Novel Horizon for Hair Cell Protection.Neural plasticity · 2021Review
- An animal model for mitochondrial tyrosyl-tRNA synthetase deficiency reveals links between oxidative phosphorylation and retinal function.The Journal of biological chemistryArticle
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12 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Defects in the posttranscriptional modifications of mitochondrial tRNAs have been linked to human diseases, but their pathophysiology remains elusive. In this report, we investigated the molecular mechanism underlying a deafness-associated tRNAIle 4295A>G mutation affecting a highly conserved adenosine at position 37, 3' adjacent to the tRNA's anticodon. Primer extension and methylation activity assays revealed that the m.4295A>G mutation introduced a tRNA methyltransferase 5 (TRMT5)-catalyzed m1G37 modification of tRNAIle. Molecular dynamics simulations suggested that the m.4295A>G mutation affected tRNAIle structure and function, supported by increased melting temperature, conformational changes and instability of mutated tRNA. An in vitro processing experiment revealed that the m.4295A>G mutation reduced the 5' end processing efficiency of tRNAIle precursors, catalyzed by RNase P. We demonstrated that cybrid cell lines carrying the m.4295A>G mutation exhibited significant alterations in aminoacylation and steady-state levels of tRNAIle. The aberrant tRNA metabolism resulted in the impairment of mitochondrial translation, respiratory deficiency, decreasing membrane potentials and ATP production, increasing production of reactive oxygen species and promoting autophagy. These demonstrated the pleiotropic effects of m.4295A>G mutation on tRNAIle and mitochondrial functions. Our findings highlighted the essential role of deficient posttranscriptional modifications in the structure and function of tRNA and their pathogenic consequence of deafness.
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