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Bioenergetics of rare diseases

ATP synthase defects represent an important subgroup of inborn errors of metabolism. It may not be surprising if we take into account that ATP synthase is one of the key energy producing enzymes in a cell. We study biogenesis of this enzyme complex and the role of various other proteins in this process.

Why study patients with mitochondrial disorders?

Mitochondria accommodate a number of key metabolic pathways including oxidative phosphorylation (OXPHOS), fatty acid beta oxidation, or Krebs cycle. It does not come as a surprise then that mitochondrial dysfunction has been recognised as an important determinant of a variety of human pathologies.

Using patient-derived samples, research into human mitochondrial pathologies has significantly contributed to discovery of new mitochondrial proteins and their functions. Taking into account that, according to current estimates, another ~300 of mitochondrial proteins are yet totally unknown, research in this field can shed light on the pathology of many diseases.

Characterisation of a new patient now typically starts with exome sequencing, which is a domain of our collaborating lab – Department of Paediatrics and Adolescent Medicine (DPAM), First Faculty of Medicine, Charles University, Prague. Our strength lies in the subsequent biochemical characterisation of the function of newly identified proteins.


ATP synthase biogenesis

Our department has a long standing tradition in studying this enzyme. We are interested in genes, whose mutations are responsible for human pathologies as well as in the biogenetic pathways leading to the assembly of this complex multisubunit enzyme.

Modular assembly of mammalian ATP synthase

Our current projects involve:

  1. The role of TMEM70 protein in ATP synthase biogenesis (Tmem70 mouse knock-outs – in collaboration with Dr. Sedlacek, IMG AS CR; Tmem70 rat knock-outs – in collaboration with Dr. Pravenec, FGU AS CR).
  1. The role of the central stalk subunits in the biogenesis of the enzyme (knock-down cell lines for subunits γ, δ and ε).
  1. Search for the new proteins associated with ATP synthase or proteins regulating enzyme biogenesis.


Supercomplexes of mitochondrial enzymes

We are interested into the associations of OXPHOS complexes into the higher structural units, so called supercomplexes. It is the rapidly evolving field and our projects cover primarily structural interactions of flavin dehydrogenases with other OXPHOS components as well as with enzymes from other pathways of mitochondrial metabolism (for example Krebs cycle).