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An In Vitro Approach to Study Mitochondrial Dysfunction: A Cybrid Model
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Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene

Xin Su1, Alain Dautant1, François Godard1

  • 1Institut de Biochimie et Génétique Cellulaires, Université de Bordeaux, 1 Rue Camille Saint-Saëns, 33077 Bordeaux, France.

International Journal of Molecular Sciences
|July 26, 2020
PubMed

Insights

Studying mitochondrial DNA (mtDNA) diseases is challenging. Using yeast, researchers identified suppressors of a pathogenic mtDNA mutation, revealing insights into ATP synthase structure and function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Mitochondrial DNA (mtDNA) mutations cause human diseases but are difficult to study due to heteroplasmy and lack of genetic manipulation methods.
  • Saccharomyces cerevisiae (yeast) serves as an excellent model organism for studying mtDNA diseases due to its genetic tractability and absence of heteroplasmy.

Purpose of the Study:

  • To investigate the functional consequences of a pathogenic mtDNA mutation (m.9191T>C) in the ATP6 gene.
  • To isolate intragenic suppressors of the m.9191T>C mutation in yeast to understand its molecular basis.

Main Methods:

  • Utilized Saccharomyces cerevisiae as a model system to study a pathogenic human mtDNA mutation (m.9191T>C) in the ATP6 gene.
  • Isolated and analyzed intragenic suppressors of the identified mutation.
  • Correlated findings with high-resolution structures of ATP synthase.

Main Results:

  • The m.9191T>C mutation, causing an amino acid change (aL222P), severely impaired yeast ATP synthase assembly and reduced ATP synthesis by 90%.
  • Intragenic suppressors of the mutation were successfully isolated.
  • Structural analysis suggests the mutation disrupts an alpha-helix bundle in subunit 'a', affecting proton conduction.

Conclusions:

  • The yeast model is effective for dissecting the molecular mechanisms of human mtDNA diseases.
  • The m.9191T>C mutation disrupts ATP synthase structure and function, impacting proton conduction.
  • Understanding these mechanisms can inform therapeutic strategies for mitochondrial diseases.
Keywords:
ATP synthaseATP6 geneCgenetic suppressorsm.9191T&gtmitochondrial DNA mutationmitochondrial diseaseproton conductionyeast

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