18.1. 2018, 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:

Kratochvilova H, Hejzlarova K, Vrbacky M, Mracek T, Karbanova V, Tesarova M, Gombitova A, Cmarko D, Wittig I, Zeman J, Houstek J. Mitochondrial membrane assembly of TMEM70 protein. Mitochondrion. 2014;15:1-9.

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.

PhD project: Impact of mitochondrial DNA diversity on metabolic phenotype and innate immunity

Recently, metabolic syndrome has been associated with chronic, low-grade systemic inflammation, increased immunogenetic susceptibility and rise in circulating immune markers. Interestingly, incidence of some of the hallmarks of metabolic syndrome (e.g. type 2 diabetes) differs among ethnicities - while part of the variability may be explained by different quality of care between ethnic groups, others seem to stem from genetic diversity. An important role may be played by physiological genetic diversity of maternally inherited mitochondrial DNA. Remarkably, mitochondria have also been demonstrated to trigger host immune response, namely by activating innate immune system.

In the current project we will utilize the model of rat conplastic strains with several mtDNA haplogroups present on identical nuclear background. We will test the hypothesis that the naturally occurring mtDNA diversity influences systemic inflammation status and further explore pathways involved in this process. Subsequently, the propensity towards development of metabolic syndrome and innate immunity response during metabolic challenge will be tested.

Candidate’s profile (requirements):

We are seeking for highly-motivated person with MSc. or equivalent degree in cell biology, biochemistry, immunology, physiology or similar field obtained before or during 2019. Candidate should be fluent in English and apart from the experimental “wet” work, she/he should be willing to work with laboratory animals.

Relevant publications:

Pecinova A, Drahota Z, Kovalcikova J, Kovarova N, Pecina P, Alan L, Zima M, Houstek J, Mracek T. Pleiotropic Effects of Biguanides on Mitochondrial Reactive Oxygen Species Production. Oxid Med Cell Longev. 2017;2017:7038603

Shabalina IG, Vrbacky M, Pecinova A, Kalinovich AV, Drahota Z, Houstek J, Mracek T, Cannon B, Nedergaard J. ROS production in brown adipose tissue mitochondria: the question of UCP1-dependence. Biochim Biophys Acta. 2014 Dec;1837(12):2017-2030

Houstek J, Hejzlarova K, Vrbacky M, Drahota Z, Landa V, Zidek V, Mlejnek P, Simakova M, Silhavy J, Miksik I, Kazdova L, Oliyarnyk O, Kurtz T, Pravenec M. Nonsynonymous variants in mt-Nd2, mt-Nd4, and mt-Nd5 are linked to effects on oxidative phosphorylation and insulin sensitivity in rat conplastic strains. Physiol Genomics. 2012 May 1;44(9):487-94

Supervisor: RNDr. Alena Pecinová, Ph.D.