Mitochondria as a drug target in unicellular human parasites

Parasitic protozoans (e.g. Trypanosoma and Leishmania) bring enormous disease burden mainly in developing countries and thus they have negative effect on our collective health and economy. The diseases caused by these parasites (i.e. Human African Trypanosomiases and Leishmaniases, respectively) are labeled by World Health Organization as Neglected Tropical Diseases due to lack of efficient treatment and vaccine.

As the drug development pipeline takes approximatelly 15 - 20 years, it is extremely important to propose promising drug targets, for which the development of a lead drug will be possible. Our team focuses on validation of essential and unique metabolic properties of Trypanosoma parasites with the aim to explore them as hopeful novel targets for chemotherapeutic intervention.

The mitochondrial energy metabolism of the infectious stage of T. brucei offers an excellent target as it includes metabolic pathways, which are very different compared to mammalian host. For instance, the energy is not produced by a canonical oxidative phosphorylation but by glycolysis and probably aslo by mitochondrial substrate phosphorylation reactions, which are absent from the mammalian mitochondria. Importantly, these pathways are essential for the parasite and therefore their functional analysis may reveal their potential as drug targets in T. brucei.

Since the normal respiratory chain is not functioning in the parasite’s mitochondrion, the essential mitochondrial membrane potential is kept by a hydrolytic activity of the FoF1 ATPase complex. In majority of eukaryotes this splendid molecular machine creates majority of ATP in the cell while in the parasitic cells it works in reverse hydrolyzing ATP to pump proton across the mitochondrial inner membrane. We showed that inhibition of such reverse activity is lethal for the parasites, but does not affect mammalian cells. This observation prompted us to explore this protein nanomotor in more details. We are interested in its composition, structure, regulation and inhibition. To reach these goals we are employing various methods e.g. crystallography, cryo-3D EM imaging, yeast two hybrid, RNAi interference, affinity purifications and others. Moreover as the T. brucei F_oF₁ ATPase exhibitis dramatic differences compared to 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. 

Author: RNDr. Alena Panicucci Zíková, PhD.

We acknowledge the use of research infrastructure that has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 316304.

This issue is processed eg. in:

Šubrtová K, Panicucci B, Zíková A. ATPaseTb2, a unique membrane-bound FoF1-ATPase component, is essential in bloodstream and dyskinetoplastic trypanosomes. PLoS Pathog. 2015 Feb 25;11(2):e1004660.

Gnipová A, Šubrtová K, Panicucci B, Horváth A, Lukeš J, Zíková A. The ADP/ATP  carrier and its relationship to oxidative phosphorylation in ancestral protist Trypanosoma brucei. Eukaryot Cell. 2015 Mar;14(3):297-310

Zíková A., Oborník M., Lukeš J. 2015: Fancy a gene? A surprisingly complex evolutionary history of peroxiredoxins. Microbial Cell 2.

Verner Z, Basu S, Benz C, Dixit S, Dobáková E, Faktorová D, Hashimi H, Horáková E, Huang Z, Paris Z, Pe?a-Diaz P, Ridlon L, Týč J, Wildridge D, Zíková A, Lukeš J. Malleable mitochondrion of Trypanosoma brucei. Int Rev Cell Mol Biol. 2015;315:73-151.