Arrested Oocyst Maturation in Plasmodium Parasites Lacking Type II NADH:Ubiquinone Dehydrogenase

Katja E Boysen,Kai Matuschewski

doi:10.1074/jbc.m111.269399

Katja E Boysen, Kai Matuschewski

Open Access

https://doi.org/10.1074/jbc.m111.269399

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Abstract

The Plasmodium mitochondrial electron transport chain has received considerable attention as a potential target for new antimalarial drugs. Atovaquone, a potent inhibitor of Plasmodium cytochrome bc(1), in combination with proguanil is recommended for chemoprophylaxis and treatment of malaria. The type II NADH:ubiquinone oxidoreductase (NDH2) is considered an attractive drug target, as its inhibition is thought to lead to the arrest of the mitochondrial electron transport chain and, as a consequence, pyrimidine biosynthesis, an essential pathway for the parasite. Using the rodent malaria parasite Plasmodium berghei as an in vivo infection model, we studied the role of NDH2 during Plasmodium life cycle progression. NDH2 can be deleted by targeted gene disruption and, thus, is dispensable for the pathogenic asexual blood stages, disproving the candidacy for an anti-malarial drug target. After transmission to the insect vector, NDH2-deficient ookinetes display an intact mitochondrial membrane potential. However, ndh2(-) parasites fail to develop into mature oocysts in the mosquito midgut. We propose that Plasmodium blood stage parasites rely on glycolysis as the main ATP generating process, whereas in the invertebrate vector, a glucose-deprived environment, the malaria parasite is dependent on an intact mitochondrial respiratory chain.

Highlights

The Plasmodium mitochondrial electron transport chain2 is a validated target for the development of antimalarial drugs (4 – 6)
It has recently been shown that short time treatment with atovaquone and proguanil exerts a stage-specific and cytostatic effect on P. falciparum blood stages in vitro [33] with ring- and schizont stages being able to survive the interruption of the mitochondrial electron transport chain (mtETC) as well as the collapse of the ⌬␺m for as long as 48 –96 h, whereas trophozoites proved to be more sensitive
In this study we addressed the in vivo role of NDH2 in the rodent malaria model parasite Plasmodium berghei

Summary

Plasmodium Alternative Type I Complex

⌬␺m does not rely exclusively on the mtETC [4]. Atovaquone, a Q analog, binds to cytochrome bcI, thereby inhibiting the reoxidization of QH2 to coenzyme Q and interrupting the mtETC. It has recently been shown that short time treatment with atovaquone and proguanil exerts a stage-specific and cytostatic effect on P. falciparum blood stages in vitro [33] with ring- and schizont stages being able to survive the interruption of the mtETC as well as the collapse of the ⌬␺m for as long as 48 –96 h, whereas trophozoites proved to be more sensitive. In this study we addressed the in vivo role of NDH2 in the rodent malaria model parasite Plasmodium berghei. Our data suggest that the Plasmodium alternative type I complex is dispensable for life cycle progression in the vertebrate host

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION