Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene - Archive ouverte HAL Access content directly
Journal Articles International Journal of Molecular Sciences Year : 2020

Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene

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Xin Su
  • Function : Author
  • PersonId : 2513
  • IdHAL : xin-su
François Godard
  • Function : Author
Marine Bouhier
  • Function : Author
Teresa Zoladek
  • Function : Author
Roza Kucharczyk
  • Function : Author
Jean-Paul Di Rago
Déborah Tribouillard-Tanvier
  • Function : Author

Abstract

Probing the pathogenicity and functional consequences of mitochondrial DNA (mtDNA) mutations from patient's cells and tissues is difficult due to genetic heteroplasmy (co-existence of wild type and mutated mtDNA in cells), occurrence of numerous mtDNA polymorphisms, and absence of methods for genetically transforming human mitochondria. Owing to its good fermenting capacity that enables survival to loss-of-function mtDNA mutations, its amenability to mitochondrial genome manipulation, and lack of heteroplasmy, Saccharomyces cerevisiae is an excellent model for studying and resolving the molecular bases of human diseases linked to mtDNA in a controlled genetic background. Using this model, we previously showed that a pathogenic mutation in mitochondrial ATP6 gene (m.9191T>C), that converts a highly conserved leucine residue into proline in human ATP synthase subunit a (aL222P), severely compromises the assembly of yeast ATP synthase and reduces by 90% the rate of mitochondrial ATP synthesis. Herein, we report the isolation of intragenic suppressors of this mutation. In light of recently described high resolution structures of ATP synthase, the results indicate that the m.9191T>C mutation disrupts a four α-helix bundle in subunit a and that the leucine residue it targets indirectly optimizes proton conduction through the membrane domain of ATP synthase.
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hal-02988568 , version 1 (04-11-2020)

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Attribution - CC BY 4.0

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Alain Dautant, Xin Su, François Godard, Marine Bouhier, Teresa Zoladek, et al.. Molecular Basis of the Pathogenic Mechanism Induced by the m.9191T>C Mutation in Mitochondrial ATP6 Gene. International Journal of Molecular Sciences, 2020, 21, ⟨10.3390/ijms21145083⟩. ⟨hal-02988568⟩

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