Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation.
Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation.
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DOI：
10.1371/journal.pone.0009582
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发表时间：
2010-03-08
期刊：
影响因子：
3.7
通讯作者：
Zhou B
中科院分区：
文献类型：
--
作者：
Wang J;Huang L;Li J;Fan Q;Long Y;Li Y;Zhou B
青蒿素是一种有效的抗疟药，其生物作用模式长期以来一直存在争议。之前，我们建立了一个酵母模型，解决其作用机制，并发现线粒体在执行青蒿素的行动的关键。在这里，我们提供的数据表明，青蒿素直接作用于线粒体，它抑制疟疾的方式类似于酵母。具体而言，青蒿素及其同系物表现出对疟疾和酵母的相关活性，过氧化物桥在这两种生物体中的抑制作用中发挥关键作用。此外，我们发现，青蒿素分布到疟疾线粒体，并直接损害其功能时，分离的线粒体进行了测试。在努力探索青蒿素的作用特异性是如何实现的，我们发现青蒿素在分离的酵母和疟疾而不是哺乳动物线粒体中诱导了惊人的快速和戏剧性的活性氧（ROS）产生，并且ROS清除剂可以改善青蒿素的作用。脱氧青蒿素缺乏内过氧化物桥，对疟疾线粒体的膜电位或ROS产生没有影响。OZ209是一种远亲抗疟疾内过氧化物，也可引起分离的疟疾线粒体中ROS的产生和去极化。最后，线粒体电子传递链（ETC）的干扰可以改变寄生虫对青蒿素的敏感性。铁螯合剂去铁胺的加入显著降低ETC活性，并减轻青蒿素诱导的ROS产生。总而言之，我们的结果表明线粒体是青蒿素抗疟作用的重要直接靶点，即使不是唯一的靶点。我们认为，从不同物种的线粒体之间的根本差异描绘了这类药物的作用特异性，并不同于许多其他药物，青蒿素的作用特异性源于其激活机制。
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.
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影响因子：
4.3
作者：
He, Su-Ping;Tan, Gui-Yu;Li, Qing X.
通讯作者：
Li, Qing X.
DOI：
10.1016/0035-9203(87)90003-4
发表时间：
1987-01-01
影响因子：
2.2
作者：
KRUNGKRAI, SR;YUTHAVONG, Y
通讯作者：
YUTHAVONG, Y
DOI：
10.1073/pnas.95.25.14681
发表时间：
1998-12-08
影响因子：
11.1
作者：
Narita, M;Shimizu, S;Tsujimoto, Y
通讯作者：
Tsujimoto, Y
影响因子：
56.9
作者：
KLAYMAN, DL
通讯作者：
KLAYMAN, DL
DOI：
10.1080/00034983.1985.11811933
发表时间：
1985-01-01
影响因子：
--
作者：
ELLIS, DS;LI, ZL;WARHURST, DC
通讯作者：
WARHURST, DC