Mitochondrial tRNA-Derived Diseases
Antonia Petropoulou1, Nikolaos Kypraios1, Dimitra Rizopoulou1
1Department of Biochemistry, School of Medicine, University of Patras, 26504 Patras, Greece.
Abstract:
Mitochondrial tRNA genes are critical hotspots for pathogenic mutations and several mitochondrial diseases. They account for approximately 70-75% of disease-causing mtDNA variants despite comprising only 5-10% of the mitochondrial genome. These mutations interfere with mitochondrial translation and affect oxidative phosphorylation, resulting in remarkably heterogeneous multisystem disorders. Under this light, we systematically reviewed PubMed, Scopus, and MITOMAP databases through October 2025, indexing all clinically relevant pathogenic mt-tRNA mutations classified by affected organ systems and underlying molecular mechanisms. Approximately 500 distinct pathogenic variants were identified across all 22 mt-tRNA genes. Beyond typical syndromes like MELAS, MERRF, Leigh syndrome, and Kearns-Sayre syndrome that are linked to mt-tRNA mutations, they increasingly implicate cardiovascular diseases (cardiomyopathy, hypertension), neuromuscular disorders (myopathies, encephalopathies), sensory impairment (hearing loss, optic neuropathy), metabolic dysfunction (diabetes, polycystic ovary syndrome), renal disease, neuropsychiatric conditions, and cancer. Beyond sequence mutations, defects in post-transcriptional modification systems emerge as critical disease mechanisms affecting mt-tRNA function and stability. The mutations on tRNA genes described herein represent potential targets for emerging genome editing therapies, although several translational challenges remain. However, targeted correction of pathogenic mt-tRNA mutations holds transformative potential for precision intervention on mitochondrial diseases.
Insights
Mitochondrial tRNA gene mutations cause numerous diseases by disrupting protein production. This review details 500 variants, highlighting their broad impact and potential for gene editing therapies.
Area of Science:
- Genetics and Molecular Biology
- Mitochondrial Biology
- Genomic Medicine
Background:
- Mitochondrial tRNA (mt-tRNA) genes are hotspots for mutations causing mitochondrial diseases.
- These mutations account for 70-75% of pathogenic mtDNA variants, impacting oxidative phosphorylation and leading to multisystem disorders.
- Understanding these variants is crucial for diagnosing and treating complex genetic conditions.
Purpose of the Study:
- To systematically review and classify clinically relevant pathogenic mt-tRNA mutations.
- To analyze the affected organ systems and underlying molecular mechanisms of these mutations.
- To explore the potential of genome editing for treating mt-tRNA-related diseases.
Main Methods:
- Systematic literature review of PubMed, Scopus, and MITOMAP databases up to October 2025.
- Indexing of pathogenic mt-tRNA mutations based on clinical relevance, affected organ systems, and molecular mechanisms.
- Identification and cataloging of distinct pathogenic variants across all 22 mt-tRNA genes.
Main Results:
- Approximately 500 distinct pathogenic mt-tRNA variants were identified.
- Mutations implicate a wide range of conditions beyond classic syndromes, including cardiovascular, neuromuscular, sensory, metabolic, renal, neuropsychiatric, and oncological diseases.
- Defects in post-transcriptional modification systems represent critical disease mechanisms alongside sequence mutations.
Conclusions:
- Pathogenic mt-tRNA mutations are implicated in a diverse spectrum of human diseases.
- Targeted genome editing therapies show promise for precision intervention in mitochondrial diseases, despite current translational challenges.
- Further research into mt-tRNA mutation mechanisms and therapeutic correction is warranted.
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