Blog
About

  • Record: found
  • Abstract: found
  • Article: found
Is Open Access

Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation

Read this article at

Bookmark
      There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

      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.

      Related collections

      Most cited references 26

      • Record: found
      • Abstract: found
      • Article: not found

      Human malaria parasites in continuous culture.

      Plasmodium falciparum can now be maintained in continuous culture in human erythrocytes incubated at 38 degrees C in RPMI 1640 medium with human serum under an atmosphere with 7 percent carbon dioxide and low oxygen (1 or 5 percent). The original parasite material, derived from an infected Aotus trivirgatus monkey, was diluted more than 100 million times by the addition of human erythrocytes at 3- or 4-day intervals. The parasites continued to reproduce in their normal asexual cycle of approximately 48 hours but were no longer highly synchronous. The have remained infective to Aotus.
        Bookmark
        • Record: found
        • Abstract: found
        • Article: not found

        Qinghaosu (artemisinin): an antimalarial drug from China.

         D L Klayman (1985)
        The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This compound, called qinghaosu (QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          Qinghaosu (artemisinin): the price of success.

           Andrew White (2008)
          Artemisinin and its derivatives have become essential components of antimalarial treatment. These plant-derived peroxides are unique among antimalarial drugs in killing the young intraerythrocytic malaria parasites, thereby preventing their development to more pathological mature stages. This results in rapid clinical and parasitological responses to treatment and life-saving benefit in severe malaria. Artemisinin combination treatments (ACTs) are now first-line drugs for uncomplicated falciparum malaria, but access to ACTs is still limited in most malaria-endemic countries. Improved agricultural practices, selection of high-yielding hybrids, microbial production, and the development of synthetic peroxides will lower prices. A global subsidy would make these drugs more affordable and available. ACTs are central to current malaria elimination initiatives, but there are concerns that tolerance to artemisinins may be emerging in Cambodia.
            Bookmark

            Author and article information

            Affiliations
            [1 ]The 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
            Charité-Universitätsmedizin Berlin, Germany
            Author notes

            Conceived and designed the experiments: JW BZ. Performed the experiments: JW LH JL QF YL. Analyzed the data: JW JL BZ. Contributed reagents/materials/analysis tools: YL. Wrote the paper: JW BZ.

            Contributors
            Role: Editor
            Journal
            PLoS One
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2010
            8 March 2010
            : 5
            : 3
            2833198
            20221395
            09-PONE-RA-13995
            10.1371/journal.pone.0009582
            (Editor)
            Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 12
            Categories
            Research Article
            Microbiology/Parasitology
            Infectious Diseases/Antimicrobials and Drug Resistance
            Infectious Diseases/Tropical and Travel-Associated Diseases
            Infectious Diseases/Antimicrobials and Drug Resistance
            Microbiology/Parasitology

            Uncategorized

            Comments

            Comment on this article