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Published on: November 11, 2014
Probing the pathogenicity of patient-derived variants of MT-ATP6 in yeast
Emilia Baranowska1, Katarzyna Niedzwiecka1, Chiranjit Panja1
1Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02106 Warsaw, Poland.
Abstract:
The list of mitochondrial DNA (mtDNA) variants detected in individuals with neurodegenerative diseases is constantly growing. Evaluating their functional consequences and pathogenicity is not easy, especially when they are found in only a limited number of patients together with wild-type mtDNA (heteroplasmy). Owing to its amenability to mitochondrial genetic transformation and incapacity to stably maintain heteroplasmy, and the strong evolutionary conservation of the proteins encoded in mitochondria, Saccharomyces cerevisiae provides a convenient model to investigate the functional consequences of human mtDNA variants. We herein report the construction and energy-transducing properties of yeast models of eight MT-ATP6 gene variants identified in patients with various disorders: m.8843T>C, m.8950G>A, m.9016A>G, m.9025G>A, m.9029A>G, m.9058A>G, m.9139G>A and m.9160T>C. Significant defect in growth dependent on respiration and deficits in ATP production were observed in yeast models of m.8950G>A, m.9025G>A and m.9029A>G, providing evidence of pathogenicity for these variants. Yeast models of the five other variants showed very mild, if any, effect on mitochondrial function, suggesting that the variants do not have, at least alone, the potential to compromise human health.
Insights
Researchers used yeast models to assess the pathogenicity of mitochondrial DNA (mtDNA) variants linked to neurodegenerative diseases. Three variants (m.8950G>A, m.9025G>A, m.9029A>G) showed significant defects, indicating they are pathogenic.
Area of Science:
- Mitochondrial genetics
- Neurodegenerative disease research
- Yeast as a model organism
Background:
- Mitochondrial DNA (mtDNA) variants are increasingly linked to neurodegenerative diseases.
- Assessing the pathogenicity of mtDNA variants, especially in heteroplasmic cases, is challenging.
Purpose of the Study:
- To investigate the functional consequences and pathogenicity of eight specific MT-ATP6 gene variants found in patients with various disorders.
- To utilize Saccharomyces cerevisiae as a model system for studying human mtDNA variant effects.
Main Methods:
- Construction of yeast models expressing eight distinct human MT-ATP6 gene variants.
- Analysis of energy-transducing properties, including respiratory growth and ATP production, in the engineered yeast strains.
Main Results:
- Yeast models of m.8950G>A, m.9025G>A, and m.9029A>G variants exhibited significant defects in respiration-dependent growth and ATP production.
- The other five variants showed minimal impact on yeast mitochondrial function, suggesting limited pathogenicity when present alone.
Conclusions:
- The study provides evidence for the pathogenicity of the m.8950G>A, m.9025G>A, and m.9029A>G mitochondrial DNA variants.
- Yeast models are effective for evaluating the functional impact of human mtDNA variants, aiding in the understanding of neurodegenerative disease mechanisms.
