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Arrested oocyst maturation in Plasmodium parasites lacking type II NADH:ubiquinone dehydrogenase
Katja E Boysen1, Kai Matuschewski
1Parasitology Unit, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
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.
Insights
The malaria parasite's NDH2 enzyme is not essential for blood stages, making it a poor drug target. However, it is crucial for parasite development in mosquitoes, highlighting a potential vulnerability in the insect vector.
Area of Science:
- * Parasitology
- * Molecular Biology
- * Drug Discovery
Background:
- * The Plasmodium mitochondrial electron transport chain is a key target for antimalarial drugs.
- * Atovaquone targets Plasmodium cytochrome bc(1), and NDH2 is a potential drug target due to its role in the electron transport chain and pyrimidine biosynthesis.
Purpose of the Study:
- * To investigate the role of type II NADH:ubiquinone oxidoreductase (NDH2) in the Plasmodium berghei life cycle.
- * To evaluate NDH2 as a potential drug target for malaria treatment.
Main Methods:
- * Utilized a rodent malaria parasite Plasmodium berghei as an in vivo infection model.
- * Employed targeted gene disruption to create NDH2-deficient parasites.
- * Analyzed parasite development in both mammalian blood stages and insect vectors.
Main Results:
- * NDH2 is dispensable for the asexual blood stages of Plasmodium, as demonstrated by successful gene deletion.
- * NDH2-deficient parasites (ndh2(-)) fail to develop into mature oocysts in the mosquito midgut, despite maintaining mitochondrial membrane potential.
- * Plasmodium blood stages primarily rely on glycolysis for ATP generation.
Conclusions:
- * NDH2 is not a viable drug target for antimalarial therapies aimed at the blood stages of the parasite.
- * The malaria parasite depends on an intact mitochondrial respiratory chain, specifically NDH2, for development in the glucose-limited environment of the invertebrate vector.
- * Targeting NDH2 could be a strategy for blocking malaria transmission by preventing oocyst development in mosquitoes.
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