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Antimicrobial Agents and Chemotherapy, January 2008, p. 164-170, Vol. 52, No. 1
0066-4804/08/$08.00+0 doi:10.1128/AAC.00378-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Anaerobic NADH-Fumarate Reductase System Is Predominant in the Respiratory Chain of Echinococcus multilocularis, Providing a Novel Target for the Chemotherapy of Alveolar Echinococcosis
Jun Matsumoto,1
Kimitoshi Sakamoto,2*
Noriko Shinjyo,2
Yasutoshi Kido,2
Nao Yamamoto,1
Kinpei Yagi,3
Hideto Miyoshi,4
Nariaki Nonaka,1
Ken Katakura,1
Kiyoshi Kita,2 and
Yuzaburo Oku1
Laboratory of Parasitology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan,1 Department of Biomedical Chemistry, Graduate School of Medicine, University of Tokyo, Tokyo, Japan,2 Department of Medical Zoology, Hokkaido Institute of Public Health, Sapporo, Japan,3 Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan4
Received 20 March 2007/ Returned for modification 21 June 2007/ Accepted 10 October 2007
Alveolar echinococcosis, which is due to the massive growth of larval Echinococcus multilocularis, is a life-threatening parasitic zoonosis distributed widely across the northern hemisphere. Commercially available chemotherapeutic compounds have parasitostatic but not parasitocidal effects. Parasitic organisms use various energy metabolic pathways that differ greatly from those of their hosts and therefore could be promising targets for chemotherapy. The aim of this study was to characterize the mitochondrial respiratory chain of E. multilocularis, with the eventual goal of developing novel antiechinococcal compounds. Enzymatic analyses using enriched mitochondrial fractions from E. multilocularis protoscoleces revealed that the mitochondria exhibited NADH-fumarate reductase activity as the predominant enzyme activity, suggesting that the mitochondrial respiratory system of the parasite is highly adapted to anaerobic environments. High-performance liquid chromatography-mass spectrometry revealed that the primary quinone of the parasite mitochondria was rhodoquinone-10, which is commonly used as an electron mediator in anaerobic respiration by the NADH-fumarate reductase system of other eukaryotes. This also suggests that the mitochondria of E. multilocularis protoscoleces possess an anaerobic respiratory chain in which complex II of the parasite functions as a rhodoquinol-fumarate reductase. Furthermore, in vitro treatment assays using respiratory chain inhibitors against the NADH-quinone reductase activity of mitochondrial complex I demonstrated that they had a potent ability to kill protoscoleces. These results suggest that the mitochondrial respiratory chain of the parasite is a promising target for chemotherapy of alveolar echinococcosis.
* Corresponding author. Mailing address: Department of Biomedical Chemistry, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan. Phone: 81 3 58418202. Fax: 81 3 58413444. E-mail: sakamok{at}m.u-tokyo.ac.jp
Published ahead of print on 22 October 2007.
Antimicrobial Agents and Chemotherapy, January 2008, p. 164-170, Vol. 52, No. 1
0066-4804/08/$08.00+0 doi:10.1128/AAC.00378-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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