Laboratoř funkční biologie protist
Parasitic protists (i.e., Trypanosoma and Leishmania) have an enormous negative effect on our collective health and economy. These parasites have developed a wide variety of physiological functions to survive within the specialized environments of their hosts. Regarding mitochondrial energy metabolism, which represents a crucial survival factor, parasites adapt to different energy sources and oxygen concentration. Thus, mitochondrial functions exhibit many unique features and interesting variations to the mammalian system. It is a focus of our lab to understand these unique properties and adaptions and to explore them as promising novel targets for chemotherapeutic intervention
Řešené výzkumné projekty
Mitochondrial respiratome of T. brucei
T. brucei mitochondrial respiratomeincludes mt inner membrane respiratory complexes I – IV together with FoF1 ATPsynthase/ATPase and important carriers e.g. ATP/ADP carrier (AAC) and phosphate carrier (PiC). There are several important reasons why to study this complex assembly of protein complexes in these unicellular flagellates; i) the composition of the mt respiratome is extreme as these protein complexes contain many novel and unique subunits; iii) the abundance, activity and function of the T. brucei respiratory complexes is developmentally regulated being fully active in the procyclic cells and absent or down-regulated in the bloodstream cells; iii) the mt FoF1 ATPase maintains the mt membrane potential (ΔΨ)in BF cells and thus possesses unique, essential and irreplaceable function in the infectious stage of the parasite.
FoF1 ATP synthase/ATPase function, structure, composition and regulation
This project involves exploitation of FoF1 ATPsynthase/ATPase complex in T. brucei by solving the F1 ATPase crystal structure, by solving the overall FoF1 structure using cryo-EM, by mapping protein-protein interaction within the complex using yeast-two hybrid and yeast complementation system. Moreover, we are expanding our functional studies to define the FoF1 ATPase role in mt cristae biogenesis and thus microenvironment formation, and in shaping the permeability transition pore. As this enzyme exhibits dramatic differences compared to the conventional complexes found in mammalian, fungal and plant mitochondria, our findings have significant implications regarding the origin and evolution of this central player of cellular bioenergetics.
Bioenergetics of bloodstream mitochondrion
We are revisiting the proposed model of bloodstream mitochondrial bioenergetics which promotes dependence on glycolytic ATP and overall low activity of mt functions in the infectious stage of the parasites. It is plausible to speculate that bloodstream mitochondria might be active in ATP production by substrate phosphorylation and thus these mt biochemical pathways, which were thought to be inactive, are present, active and essential for the parasite. Therefore, the functional analysis of these pathways may reveal their potential as drug targets against T. brucei parasites.
Mechanism of mode of action of trypanocidal compounds in relation to the mitochondrial function
In collaboration with several scientific group, we are interested in identifying mode of action of some promising trypanocidal compounds. These compounds usually affect mt function. With a plethora of phenotypic assays we are able to decipher or point towards the drug target and mechanism of action.