Dataset Information

The Mitochondrial tRNA^Phe 625G>A Mutation in Three Han Chinese Families With Cholecystolithiasis.

ABSTRACT: In this study, we assessed three Chinese families with inherited cholecystolithiasis and conducted the clinical, genetic, and molecular characterization of these subjects. Eight of eighteen matrilineal relatives had a clinical phenotype in these three families. Sequence analysis of complete mitochondrial genomes in these probands identified the homoplasmic tRNA^Phe 625 G > A mutation and distinct sets of mtDNA polymorphisms belonging to haplogroups H2, F4b, and M10a. The 625G > A mutation disturbed the classic G-C base-pairings at a highly conserved position 49 in the T-stem of mitochondrial tRNAs. Molecular dynamics simulation showed that the structure of tRNA^phe with 625 G > A mutation was noticeably remodeled while compared with the isoform of the wild type. The occurrence of tRNA^Phe 625 G > A mutation in these various genetically unrelated subjects strongly indicates that this mutation is involved in the pathogenesis of cholecystolithiasis. This is the first evidence that tRNA mutations are associated with cholecystolithiasis, and it provided more insights into the genetic mechanism of cholecystolithiasis.

SUBMITTER: Hou L

PROVIDER: S-EPMC9198646 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The Mitochondrial tRNA<sup>Phe</sup> 625G>A Mutation in Three Han Chinese Families With Cholecystolithiasis.

Hou Lingling L Hu Cuifang C Ji Lili L Wang Qiongdan Q Liang Min M

Frontiers in genetics 20220527

In this study, we assessed three Chinese families with inherited cholecystolithiasis and conducted the clinical, genetic, and molecular characterization of these subjects. Eight of eighteen matrilineal relatives had a clinical phenotype in these three families. Sequence analysis of complete mitochondrial genomes in these probands identified the homoplasmic tRNA<sup>Phe</sup> 625 G > A mutation and distinct sets of mtDNA polymorphisms belonging to haplogroups H2, F4b, and M10a. The 625G > A mutat ...[more]

PMID: 35719381

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Project description:The deafness-associated m.12201T>C mutation affects the A5-U68 base-pairing within the acceptor stem of mitochondrial tRNAHis The primary defect in this mutation is an alteration in tRNAHis aminoacylation. Here, we further investigate the molecular mechanism of the deafness-associated tRNAHis 12201T>C mutation and test whether the overexpression of the human mitochondrial histidyl-tRNA synthetase gene (HARS2) in cytoplasmic hybrid (cybrid) cells carrying the m.12201T>C mutation reverses mitochondrial dysfunctions. Using molecular dynamics simulations, we demonstrate that the m.12201T>C mutation perturbs the tRNAHis structure and function, supported by decreased melting temperature, conformational changes, and instability of mutated tRNA. We show that the m.12201T>C mutation-induced alteration of aminoacylation tRNAHis causes mitochondrial translational defects and respiratory deficiency. We found that the transfer of HARS2 into the cybrids carrying the m.12201T>C mutation raises the levels of aminoacylated tRNAHis from 56.3 to 75.0% but does not change the aminoacylation of other tRNAs. Strikingly, HARS2 overexpression increased the steady-state levels of tRNAHis and of noncognate tRNAs, including tRNAAla, tRNAGln, tRNAGlu, tRNALeu(UUR), tRNALys, and tRNAMet, in cells bearing the m.12201T>C mutation. This improved tRNA metabolism elevated the efficiency of mitochondrial translation, activities of oxidative phosphorylation complexes, and respiration capacity. Furthermore, HARS2 overexpression markedly increased mitochondrial ATP levels and membrane potential and reduced production of reactive oxygen species in cells carrying the m.12201T>C mutation. These results indicate that HARS2 overexpression corrects the mitochondrial dysfunction caused by the tRNAHis mutation. These findings provide critical insights into the pathophysiology of mitochondrial disease and represent a step toward improved therapeutic interventions for mitochondrial disorders.

Dataset Information

The Mitochondrial tRNA^Phe 625G>A Mutation in Three Han Chinese Families With Cholecystolithiasis.

Publications

The Mitochondrial tRNA<sup>Phe</sup> 625G>A Mutation in Three Han Chinese Families With Cholecystolithiasis.

Similar Datasets

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Dataset Information

The Mitochondrial tRNAPhe 625G>A Mutation in Three Han Chinese Families With Cholecystolithiasis.

Publications

The Mitochondrial tRNA<sup>Phe</sup> 625G>A Mutation in Three Han Chinese Families With Cholecystolithiasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The Mitochondrial tRNA^Phe 625G>A Mutation in Three Han Chinese Families With Cholecystolithiasis.