Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation
文献类型：期刊论文
| 作者 | Wang, Juan1; Huang, Liying1; Li, Jian1; Fan, Qiangwang1; Long, Yicheng1; Li, Ying2; Zhou, Bing1
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| 刊名 | PLOS ONE
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| 出版日期 | 2010-03-08 |
| 卷号 | 5期号:3页码:A158-A169 |
| ISSN号 | 1932-6203 |
| DOI | 10.1371/journal.pone.0009582 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | VITRO ANTIMALARIAL ACTIVITY ; PLASMODIUM-FALCIPARUM ; QINGHAOSU ARTEMISININ ; XANTHINE-OXIDASE ; COMPLEX-I ; MECHANISM ; SUPEROXIDE ; BERGHEI ; ARTESUNATE ; GENERATION |
| 资助项目 | National Scientific Foundation of China[30688001] ; National Basic Research Program of China[2005CB522503] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000275328200015 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278948]  |
| 专题 | 药物化学研究室 |
| 通讯作者 | Wang, Juan |
| 作者单位 | 1.Tsinghua Univ, Dept Biol Sci & Biotechnol, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100084, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Juan,Huang, Liying,Li, Jian,et al. Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation[J]. PLOS ONE,2010,5(3):A158-A169. |
| APA | Wang, Juan.,Huang, Liying.,Li, Jian.,Fan, Qiangwang.,Long, Yicheng.,...&Zhou, Bing.(2010).Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation.PLOS ONE,5(3),A158-A169. |
| MLA | Wang, Juan,et al."Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation".PLOS ONE 5.3(2010):A158-A169. |
入库方式： OAI收割
来源：上海药物研究所
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