Yeast Model Uncovers Dual Roles of Mitochondria in the Action of Artemisinin

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.

Synopsis

Malaria kills at least 1 million people worldwide a year. Recent years saw the rapid emergence of drug-resistant malaria strains. Artemisinins, derived from the Chinese wormwood herb Artemisia annua, are the most potent antimalarials currently available. Despite extensive research, the exact mode of action of artemisinins has not been established. In this article, Li et al. investigated yeast as a model to probe the core working mechanism of this class of antimalarials. They showed that artemisinin can disrupt the normal function of mitochondria by depolarizing its membrane potential, and that artemisinin's effect can be affected by its interaction with the mitochondrial electron transport chain, an apparatus that couples oxygen oxidation and energy generation in the cell. They proposed a dual role of mitochondria played during the action of artemisinin: the electron transport chain likely activates artemisinin, and the mitochondria are subsequently damaged by the locally generated free radicals associated with this activation. The research has provided a fine tool for the study of the mechanism of artemisinin in a model organism (yeast), and laid the framework for a set of possible future experiments to be conducted in yeast and malaria parasites.