Binko 2015 Abstract MiP2015

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Yeast as a system for modeling mitochondrial disease mechanisms and therapies.

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Binko K, Kabala A, Niedzwiecka K, Dautant A, di Rago JP, Kucharczyk R (2015)

Event: MiP2015

Mitochondria, besides the key role in bioenergetics, carry out a lot of functions essential for cell viability, thus impairment of any of them can result in a wide spectrum of severe abnormalities in humans known as mitochondrial diseases. The diagnosis is difficult due to multiplicity of clinical manifestation depending on involved function and affected tissues. Additionally it is complicated by heteroplasmy of mitochondrial DNA (mtDNA) in human cells. The yeast Saccharomyces cerevisiae is the organism of choice to uncover cellular and molecular mechanisms underlying the mitochondrial diseases. The most important is the capability to use fermentable carbon substrates as energy source, resulting in ability to survive even when mtDNA has been completely depleted. What more, site-direct mutagenesis of yeast mtDNA is possible by biolistic transformation and the population of mutated mtDNA will be 100% homoplasmic.

ATP synthase is multi-subunit enzyme located in inner mitochondrial membrane. The enzyme uses the energy provided by the proton electrochemical gradient as a force to drive ATP synthesis. Point mutations in ATP6 gene were identified in patients suffering the neurological defects.

The mitochondrially encoded Atp6 subunit of ATP synthase is evolutionary conserved, therefore it is possible to create yeast models of human diseases bearing the particular pathogenic mutations for analysis of their consequences. Here we present the results of systematic investigation on cellular effects of 9 pathogenic mutations introduced to ATP6 gene of S. cerevisiae leading in human to Neurogenic Ataxia and Retinitis Pigmentosa (NARP), Leigh syndrome (LS), Charcot-Marie-Tooth (CMT), NARP or Familial Bilateral Striatal Necrosis (FBSN) syndromes.

Importantly, chemical screens of drugs using yeast have pointed to potential therapeutic targets. Through selection of intragenic revertants in respiratory deficient mutants of ATP6 gene, the identification of amino acids important for the mechanism of proton transport was possible. Thus from study of the pathogenic mutations yeast has brought us to the fundamental mechanism of the enzyme function.


O2k-Network Lab: FR Bordeau Di Rago JP


Labels: MiParea: mt-Membrane, mtDNA;mt-genetics, Patients 

Stress:Mitochondrial disease  Organism: Saccharomyces cerevisiae 




Event: A1, Poster  MiP2015 

Affiliations

1-Dept Genetics, Inst Biochem Biophysics, Polish Academy of Sc, Warsaw, Poland; 2-Univ Bordeaux-CNRS, IBGC, UMR 5095, 1 rue Camille Saint-Saëns, Bordeaux, France. - krystynabin@ibb.waw.pl