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Updated: Dec 26, 2025
Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing
Published on: February 10, 2023
Systematic analysis of a mitochondrial disease-causing ND6 mutation in mitochondrial deficiency
Deyu Chen1, Qiongya Zhao2, Jingting Xiong3
1Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, China.
Background:
The m.14487T>C mutation is recognized as a diagnostic mutation of mitochondrial disease during the past 16 years, emerging evidence suggests that mutant loads of m.14487T>C and disease phenotype are not closely correlated.
Methods:
Immortalized lymphocytes were generated by coculturing the Epstein-Barr virus and lymphocytes from m.14487T>C carrier Chinese patient with Leigh syndrome. Fifteen cytoplasmic hybrid (cybrid) cell lines were generated by fusing mtDNA lacking 143B cells with platelets donated by patients. Mitochondrial function was systematically analyzed at transcriptomic, metabolomic, and biochemical levels.
Results:
Unlike previous reports, we found that the assembly of mitochondrial respiratory chain complexes, mitochondrial respiration, and mitochondrial OXPHOS function was barely affected in cybrid cells carrying homoplastic m.14487T>C mutation. Mitochondrial dysfunction associated transcriptomic and metabolomic reprogramming were not detected in cybrid carrying homoplastic m.14487T>C. However, we found that mitochondrial function was impaired in patient-derived immortalized lymphocytes.
Conclusion:
Our data revealed that m.14487T>C mutation is insufficient to cause mitochondrial deficiency; additional modifier genes may be involved in m.14487T>C-associated mitochondrial disease. Our results further demonstrated that a caution should be taken by solely use of m.14487T>C mutation for molecular diagnosis of mitochondrial disease.
Insights
The m.14487T>C mutation alone does not cause mitochondrial disease. Additional genetic factors likely influence disease severity, suggesting caution in using this mutation solely for diagnosing mitochondrial disorders.
Area of Science:
- Mitochondrial genetics
- Molecular biology
- Human genetics
Background:
- The m.14487T>C mutation is a known diagnostic marker for mitochondrial disease.
- Emerging evidence indicates a weak correlation between m.14487T>C mutant load and disease phenotype.
Purpose of the Study:
- To investigate the direct impact of the m.14487T>C mutation on mitochondrial function.
- To explore the role of modifier genes in m.14487T>C-associated mitochondrial disease.
Main Methods:
- Generated immortalized lymphocytes from a Chinese patient with Leigh syndrome carrying the m.14487T>C mutation.
- Created cytoplasmic hybrid (cybrid) cell lines by fusing cells with and without the mutation.
- Analyzed mitochondrial function at transcriptomic, metabolomic, and biochemical levels.
Main Results:
- Homoplastic m.14487T>C mutation showed minimal impact on mitochondrial respiratory chain complexes, respiration, and OXPHOS function in cybrid cells.
- No transcriptomic or metabolomic reprogramming indicative of mitochondrial dysfunction was observed in cybrid cells with homoplastic m.14487T>C.
- Mitochondrial function was impaired in patient-derived immortalized lymphocytes, suggesting other factors are involved.
Conclusions:
- The m.14487T>C mutation is insufficient to cause mitochondrial deficiency on its own.
- Additional genetic modifiers likely contribute to m.14487T>C-associated mitochondrial disease.
- Sole reliance on the m.14487T>C mutation for molecular diagnosis of mitochondrial disease warrants caution.
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