artemisinin directly targets malarial mitochondria through its specific mitochondrial activation青蒿素的直接目标疟疾线粒体通过其特定的线粒体激活.pdfVIP

Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation 1 1 1 1 1 2 1 Juan Wang , Liying Huang , Jian Li , Qiangwang Fan , Yicheng Long , Ying Li , Bing Zhou * 1The State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China, 2 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China 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 a