Cutting-edge science for health

Molecular mechanisms of pathogenicity in ATP synthase disorders

Laboratory of Bioenergetics

PhD project: Molecular mechanisms of pathogenicity in ATP synthase disorders

Mutations in mitochondrial FoF1 ATP synthase lead to severe inborn errors of metabolism. As is the case with other mitochondrial diseases, one of the striking features is the tissue specificity of symptoms associated with mutations in individual subunits. Thus, mutations in TMEM70 or ATP5E present primarily as myopathies, while Usmg5 patients present with neurological disorders. While the primary biochemical features are generally characterised, mechanisms dictating tissue specificity are still poorly understood.

Recently, we have developed animal models for defects in TMEM70 as well as Usmg5. The aim of this project is to explore differences in tissue presentation as well as compensatory or regulatory mechanisms involved to mitigate pathogenic phenotype. The project should aim beyond the biochemical characterisation of mitochondrial function and dig further into the adaptations occurring at the whole body level to understand the role of ATP synthase in modulation of metabolic plasticity. This project should take the advantage of wide array of phenotypisation techniques available at the Institute of Physiology and adapt them for the use on mitochondrial models.

Candidate’s profile (requirements): MSc or MD degree in (animal) physiology or similar. Candidates should have a good record of accomplishment in physiology and biochemistry. Willingness to work with laboratory animals is requirement, previous experience strong asset.

Relevant publications:

1.   Kovalčíková J, Vrbacký M, Pecina P, Tauchmannová K, Nůsková H, Kaplanová V, Brázdová A, Alán L, Eliáš J, Čunátová K, Kořínek V, Sedlacek R, Mráček T, Houštěk J.: TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme. FASEB J. 2019 Dec;33(12):14103-14117

2.   Vrbacky M, Kovalcikova J, Chawengsaksophak K, Beck IM, Mracek T, Nuskova H, Sedmera D, Papousek F, Kolar F, Sobol M, Hozak P, Sedlacek R, Houstek J. Knockout of Tmem70 alters biogenesis of ATP synthase and leads to embryonal lethality in mice. Hum Mol Genet. 2016;25(21):4674-85.

Supervisor: RNDr. Tomáš Mráček, Ph.D.