Li W~Zhou B, 2005

Pubmed ID 16170412
Title Yeast model uncovers dual roles of mitochondria in action of artemisinin.
Authors Wei Li, Weike Mo, Dan Shen, Libo Sun, Juan Wang, Shan Lu, Jane M Gitschier, Bing Zhou
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.
Citation PLoS Genet. 2005; 1:e36
Data abstract Deletion collection was tested for resistance to artemisinin.

Datasets

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Paper Phenotype Condition Medium Collection Tested mutants Data Details
Li W~Zhou B, 2005 growth (pooled CFU) (+)-artemisinin [3-5 uM] YPG(E) hom ~4,757 Discrete

Curation history

Data

Aug. 3, 2020 Waiting for tested.
Aug. 5, 2020 Loaded.
Aug. 5, 2020 Ready to load.

Tested strains

July 10, 2020 To request.
Aug. 3, 2020 Request sent.
Aug. 5, 2020 Not available.