Unravelling the Plasmodium mitochondrion: systematic functional characterization of an essential organelle for anti-malarial drug target identification
Despite significant human effort, malaria remains one of the most impactful and deadly diseases worldwide. A major reason for this is that the causative agents of the genus Plasmodium, have evolved resistance to most common antimalarial drugs. The mitochondrion of these parasites has hallmarks of an attractive drug target as it is essential and quite distinct from host mitochondria. Precisely because it is so different from all standard mitochondrial systems, our knowledge about the functioning and makeup of this organelle in the malaria parasites is still severely lacking.
During sexual maturation the mitochondrion undergoes dramatic morphological and functional changes. The whole organelle elongates, branches out and cristae, invaginations of the inner mitochondrial membrane, become apparent. The canonical role of the mitochondrion is to provide energy for the cell through oxidative phosphorylation. This dogma does not seem to hold true for the blood stages of Plasmodium spp.. Instead their main mode of energy generation is the less efficient anaerobic glycolysis taking place in the cytoplasm. Nevertheless the parasites encode a functional TCA cycle along with the necessary parts for a functional respiratory chain. The former however is largely not required in the asexual stages and for the latter it has been found that at least complex III seems to be reduced to serving anabolic processes instead of respiration. This however changes in gametocytes and subsequent insect stages. Impairment of either TCA cycle or respiratory changes seems to significantly decrease gametocyte fitness and completely abolishes the ability to colonize the mosquito host. At the same time we currently do not have convincing evidence that the parasite has a functional ATP synthase to utilize the respiratory chain.
Overall, there are various pieces of research showing dramatic change in form and function of the mitochondrion during life cycle progression. However, detailed and systematic understanding of these changes and how they integrate and help the parasite survive, is still lacking. In my PhD project I am combining proteomic, genetic and microscopic approaches to address this gap in our knowledge and reveal mitochondrial dynamics and their functional implications across different life cycle stages of the parasite.
(The picture shows an transmission electron microscopy image of a mature P. falciparum stage V gametocyte. The inset show an enlargement of the cristate mitochodrion. Image by Felix Evers & Mariska Kea-te Lindert.)
Taco Kooij 