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Queuine ameliorates impaired mitochondrial function caused by mt-tRNAAsn variants
Yan Lin1, Jiayin Wang1, Xingyu Zhuang1
1Department of Neurology, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, No. 107 West Wenhua Road Jinan, Jinan, Shandong, 250012, China.
Journal of Translational Medicine
|August 22, 2024
Summary
Queuine supplementation shows promise for treating mitochondrial diseases caused by mitochondrial transfer RNA (mt-tRNA) Asn variants. This approach can restore mitochondrial function and improve patient outcomes.
Area of Science:
- Mitochondrial genetics and disease
- Molecular biology and tRNA modifications
- Biochemistry and cellular respiration
Background:
- Mitochondrial tRNA (mt-tRNA) variants are implicated in various human diseases.
- Post-transcriptional modification of mt-tRNA, such as queuosine (Q) incorporation, is crucial for efficient mitochondrial mRNA translation.
- Recent identification of Q modifications in mt-tRNAAsn highlights a new area of research in mitochondrial health.
Purpose of the Study:
- To investigate the therapeutic effectiveness of queuine in cellular models of patients with mt-tRNAAsn variants.
- To confirm the pathogenicity of a novel m.5708 C>T variant in mt-tRNAAsn.
- To evaluate queuine's potential to mitigate mitochondrial dysfunction associated with these variants.
Main Methods:
- Analysis of six patients from four families with identified mt-tRNAAsn variants.
- Quantification of queuine levels using mass spectrometry.
- Comprehensive clinical, genetic, histochemical, biochemical, and molecular analyses of patient-derived tissues and cell lines (LCLs).
Main Results:
- Pathogenicity of the novel m.5708 C>T mt-tRNAAsn variant confirmed through decreased mt-tRNAAsn levels, reduced protein synthesis, impaired oxygen consumption, and diminished respiratory complex activity.
- Significantly reduced serum queuine levels observed in patients carrying these variants.
- In vitro queuine supplementation successfully restored mitochondrial function, including membrane potential and oxygen consumption, while reducing reactive oxygen species.
Conclusions:
- The m.5708 C>T variant in mt-tRNAAsn is pathogenic, contributing to the understanding of mitochondrial disorders.
- Queuine supplementation emerges as a potential therapeutic strategy to stabilize mt-tRNAAsn and ameliorate mitochondrial dysfunction.
- These findings suggest promising implications for developing targeted therapies for patients with mt-tRNAAsn-related mitochondrial diseases.
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