Dataset Information

Queuine ameliorates impaired mitochondrial function caused by mt-tRNA^Asn variants.

ABSTRACT:

Background

Mitochondrial tRNA (mt-tRNA) variants have been found to cause disease. Post-transcriptional queuosine (Q) modifications of mt-tRNA can promote efficient mitochondrial mRNA translation. Q modifications of mt-tRNA^Asn have recently been identified. Here, the therapeutic effectiveness of queuine was investigated in cells from patients with mt-tRNA^Asn variants.

Methods

Six patients (from four families) carrying mt-tRNA^Asn variants were included in the study. Queuine levels were quantified by mass spectrometry. Clinical, genetic, histochemical, biochemical, and molecular analysis was performed on muscle tissues and lymphoblastoid cell lines (LCLs) from patients to investigate the pathogenicity of the novel m.5708 C > T variant. The use of queuine in mitigating mitochondrial dysfunction resulting from the mt-tRNA^Asn variants was evaluated.

Results

The variants included the m.5701 delA, m.5708 C > T, m.5709 C > T, and m.5698 G > A variants in mt-tRNA^Asn. The pathogenicity of the novel m.5708 C > T variant was confirmed, as demonstrated by a decreased steady-state level of mt-tRNA^Asn, mtDNA-encoded protein levels, oxygen consumption rate (OCR), and the respiratory complex activity. Notably, the serum queuine level was significantly reduced in these patients and in vitro queuine supplementation was found to restore the reductions in mitochondrial protein activities, mitochondrial membrane potential, OCR, and increases in reactive oxygen species.

Conclusions

The study not only confirmed the pathogenicity of the m.5708 C > T variant but also explored the therapeutic potential of queuine in individuals with mt-tRNA^Asn variants. The recognition of the novel m.5708 C > T variant's pathogenic nature contributes to our comprehension of mitochondrial disorders. Furthermore, the results emphasize queuine supplementation as a promising approach to enhance the stability of mt-tRNA^Asn and rescue mitochondrial dysfunction caused by mt-tRNA^Asn variants, indicating potential implications for the development of targeted therapies for patients with mt-tRNA^Asn variants.

SUBMITTER: Lin Y

PROVIDER: S-EPMC11340107 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Queuine ameliorates impaired mitochondrial function caused by mt-tRNA<sup>Asn</sup> variants.

Lin Yan Y Wang Jiayin J Zhuang Xingyu X Zhao Ying Y Wang Wei W Wang Dongdong D Zhao Yuying Y Yan Chuanzhu C Ji Kunqian K

Journal of translational medicine 20240822 1

<h4>Background</h4>Mitochondrial tRNA (mt-tRNA) variants have been found to cause disease. Post-transcriptional queuosine (Q) modifications of mt-tRNA can promote efficient mitochondrial mRNA translation. Q modifications of mt-tRNA<sup>Asn</sup> have recently been identified. Here, the therapeutic effectiveness of queuine was investigated in cells from patients with mt-tRNA<sup>Asn</sup> variants.<h4>Methods</h4>Six patients (from four families) carrying mt-tRNA<sup>Asn</sup> variants were inclu ...[more]

PMID: 39175050

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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

Queuine ameliorates impaired mitochondrial function caused by mt-tRNA^Asn variants.

Background

Methods

Results

Conclusions

Publications

Queuine ameliorates impaired mitochondrial function caused by mt-tRNA<sup>Asn</sup> variants.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Queuine ameliorates impaired mitochondrial function caused by mt-tRNAAsn variants.

Background

Methods

Results

Conclusions

Publications

Queuine ameliorates impaired mitochondrial function caused by mt-tRNA<sup>Asn</sup> variants.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Queuine ameliorates impaired mitochondrial function caused by mt-tRNA^Asn variants.