Yeast model uncovers dual of mitochondria in the action of artemisinin

Abstract

Artemisirtins, derived from the wormwood herb Artemisia connua, are the most potent antimalarial drugs currently avachie, Despaite extensive research, the exact mode of action of artemisinans has not been established, Here we yse yeast, Saccfaamtnyces cerevisiae, to probe the core working mechanism of this dass of arttimaiarial agents, We demonstrate that artemisinisi's inhibitory effect is mediated by disrupting the normaS function of mitochondria through depolarizing their membrane potersilal, Moreover, in a genetic study, we identify the electron transport chairs as an important piayer in artemisinin's action: DeSetion of NDE1 or NDIl, which encode mitochosidrial NADH dehydrogersases, confers resistance to artemisirllin, whereas overexpression of NDE1 or ND11 dramatically increases sensitivity to artemisinirs, Miatatiosis or envirorsmental corsditiorss that affect eiectron transport also alter host's sensitivity to artemisinin, Sensitivity is partially restored when the Plasmodium falciparum NDI1 orthoolog is expressed in yeast ndi1 strairs, Finally, we showed that artemisinin's inhibitory effect is mediated by reactive oxygen species, owr resuits demonstrate that artemisinirs's effect is primarily mediated through disruptsors of membrane potential by its interaction with the eieelron transport ehainf resisitirsg in dysfunetional mitochondria, We propose a dual role of mitochondria played durirsg the action of artemisirsin: the electron transport chain stimuiates artemisinin's effect, most likely by actavating it, and the mitochondria are subsequently damaged by the locally generated free radicals. Copyright: © 2005 Li, et al.