Abstract
Artemisinins, derived from the wormwood herb Artemisia annua, are the most potent antimalarial drugs currently available. Despite extensive research, the exact mode of action of artemisinins has not been established. Here we use yeast, Saccharamyces cerevisiae, to probe the core working mechanism of this class of antimalarial agents. We demonstrate that artemisinin's inhibitory effect is mediated by disrupting the normal function of mitochondria through depolarizing their membrane potential. Moreover, in a genetic study, we identify the electron transport chain as an important player in artemisinin's action: Deletion of NDE1 or NDI1, which encode mitochondrial NADH dehydrogenases, confers resistance to artemisinin, whereas overexpression of NDE1 or NDI1 dramatically increases sensitivity to artemisinin. Mutations or environmental conditions that affect electron transport also alter host's sensitivity to artemisinin. Sensitivity is partially restored when the Plasmodium falciparum NDI1 ortholog is expressed in yeast ndi1 strain. Finally, we showed that artemisinin's inhibitory effect is mediated by reactive oxygen species. Our results demonstrate that artemisinin's effect is primarily mediated through disruption of membrane potential by its interaction with the electron transport chain, resulting in dysfunctional mitochondria. We propose a dual role of mitochondria played during the action of artemisinin: the electron transport chain stimulates artemisinin's effect, most likely by activating it, and the mitochondria are subsequently damaged by the locally generated free radicals.
Highlights
Malaria, the most prevalent and pernicious parasitic disease of humans, is estimated to kill between 1 million and 2 million people, mainly children, each year
In order to determine whether artemisinin interferes with mitochondrial function, yeast was grown in YPG or YPE media in which glucose was replaced with the nonfermentable carbon source glycerol or ethanol
We demonstrated that artemisinin is able to depolarize the mitochondrial membrane and that increased electron transport activity increases the sensitivity of the cell to artemisinin
Summary
The most prevalent and pernicious parasitic disease of humans, is estimated to kill between 1 million and 2 million people, mainly children, each year. The mechanism of the action of artemisinin remains a mystery, iron appears to be involved in activating this endoperoxide to generate cytotoxic free radicals [1]. Several candidates have been hypothesized as targets of artemisinins, including haem, a translationally controlled tumor protein and some parasite membrane proteins [1,2,3], but none of these have been convincingly shown to be functionally relevant. One important reason for the lack of satisfying progress in understanding artemisinin is that it is difficult to carry out genetic analysis of malaria parasites. The yeast Saccharamyces cerevisiae is an ideal model organism to uncover a variety of molecular mechanisms that otherwise might be difficult to address with other systems. We developed a yeast model and used it to probe the fundamental mechanisms of artemisinin’s action
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