Essential functions of the mitochondrion in malaria parasites

PROJECT SUMMARY Malaria is a devastating disease that impacts millions of people on an annual basis. While several species of Plasmodium parasites cause malaria in humans, P. falciparum is responsible for the highest rates of complications and mortality. Malaria elimination efforts are continually challenged by the emergence and spread of resistant P. falciparum strains to frontline chemotherapies. New treatments targeting alternative molecular targets in the parasite are therefore urgently needed. An ideal antimalarial drug should exhibit prophylactic, curative and transmission blocking properties. However, few clinically approved drugs fit this profile due to a two-fold problem: 1) many genes that are essential in mosquito or liver stage parasites are dispensable in symptomatic blood stages, making it hard to identify a drug target that is relevant throughout the parasite life cycle; 2) the field has historically suffered from a dearth of robust genetic tools to investigate basic parasite biology, a prerequisite for uncovering novel therapeutic approaches. In response to these challenges, we propose using new and improved genetic methods to expand the druggable parasite proteome across all stages of infection. We will focus our efforts on the parasite mitochondrion, a promising source of drug targets since it is essential in all parasite life stages and is highly divergent from its human counterpart. This organelle’s potential as an antimalarial target has already been validated by atovaquone, the only mitochondrial inhibitor in clinical use. Notably, atovaquone belongs to the very small group of drugs that are active against both symptomatic and transmission stages of infection. The mitochondrion contains nearly 10% of the total parasite proteome, the majority of which has no known function. Identifying essential processes within the mitochondrion can pave the way for the development of new drugs that not only prevent or treat malaria but also block transmission.