Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation

Abstract

The biological mode of action of artemisinin, a potent antimalarial, has long been controversial. Previously we established a yeast model addressing its mechanism of action and found mitochondria the key in executing artemisinin's action. Here we present data showing that artemisinin directly acts on mitochondria and it inhibits malaria in a similar way as yeast. Specifically, artemisinin and its homologues exhibit correlated activities against malaria and yeast, with the peroxide bridge playing a key role for their inhibitory action in both organisms. In addition, we showed that artemisinins are distributed to malarial mitochondria and directly impair their functions when isolated mitochondria were tested. In efforts to explore how the action specificity of artemisinin is achieved, we found strikingly rapid and dramatic reactive oxygen species (ROS) production is induced with artemisinin in isolated yeast and malarial but not mammalian mitochondria, and ROS scavengers can ameliorate the effects of artemisinin. Deoxyartemisinin, which lacks an endoperoxide bridge, has no effect on membrane potential or ROS production in malarial mitochondria. OZ209, a distantly related antimalarial endoperoxide, also causes ROS production and depolarization in isolated malarial mitochondria. Finally, interference of mitochondrial electron transport chain (ETC) can alter the sensitivity of the parasite towards artemisinin. Addition of iron chelator desferrioxamine drastically reduces ETC activity as well as mitigates artemisinin-induced ROS production. Taken together, our results indicate that mitochondrion is an important direct target, if not the sole one, in the antimalarial action of artemisinins. We suggest that fundamental differences among mitochondria from different species delineate the action specificity of this class of drugs, and differing from many other drugs, the action specificity of artemisinins originates from their activation mechanism.

Efficacy of artemether-lumefantrine in treatment of malaria among under-fives and prevalence of drug resistance markers in Igombe-Mwanza, north-western Tanzania

“…Hunt et al, 2009 reports that analysis of studies in East Africa shows that the parasites were being controlled less well by the artemisinin component of ACT in 2007/ 2008 studies than in 2005/2006 [12]. As these reports are coming up, the mechanism of action of artemisinin is not known yet, a few target genes have been suggested with inconclusive findings [13][14][15][16]. Treatment with AL has led to selection of wild type alleles at molecular markers for CQ resistance (pfcrt 76 K and pfmdr1 86 N) with a concomitant reduction in susceptibility to lumefantrine [17].…”

The Role of Heme and the Mitochondrion in the Chemical and Molecular Mechanisms of Mammalian Cell Death Induced by the Artemisinin Antimalarials

“…Elegant studies performed with a yeast model and isolated mitochondria of parasite and mammalian cell origin have suggested that, in contrast to the iron activation theory, the mitochondrion may be a direct target and mediator of endoperoxide activity and further may underlie selectivity to the parasite (27,28). The authors of these studies hypothesized that the mitochondria play a dual role: the electron transport chain (ETC) delivers reducing equivalents for activation of the endoperoxide function and, as a consequence, the mitochondria are damaged; ROS are generated leading to the eventual induction of parasite death.…”

Qinghaosu (artemisinin): Chemistry and pharmacology

“…Up to now, a growing list shows that heme, heme-containing protein, translationally controlled tumor-associated protein (TCTP), sarcoendoplasmic reticulum Ca 2+ ATPase (SERCA)-type protein encoded by PfATP6 might be the targets [14] . Recently, Chinese researchers reported that artemisinins are distributed to malarial mitochondria and directly impair their functions [29] .…”