Anaerobic NADH-fumarate reductase system is predominant in the respiratory chain of Echinococcus multilocularis, providing a novel target for the chemotherapy of alveolar echinococcosis
Anaerobic NADH-fumarate reductase system is predominant in the respiratory chain of Echinococcus multilocularis, providing a novel target for the chemotherapy of alveolar echinococcosis
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DOI：
10.1128/aac.00378-07
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发表时间：
2008-01-01
影响因子：
4.9
通讯作者：
Oku, Yuzaburo
中科院分区：
文献类型：
--
作者：
Matsumoto, Jun;Sakamoto, Kimitoshi;Oku, Yuzaburo
泡状棘球蚴病是由多房棘球蚴幼虫大量生长引起的一种危及生命的寄生虫病，广泛分布于北方。市售的化疗化合物具有抑制寄生虫的作用，但不具有杀寄生虫的作用。寄生生物使用各种能量代谢途径，这些途径与其宿主的代谢途径有很大不同，因此可能是有希望的化疗靶点。本研究的目的是表征线粒体呼吸链的E。multilocularis，最终目标是开发新的抗棘球蚴化合物。利用富集的线粒体组分进行酶分析。multicularis protoplecies的线粒体显示NADH-延胡索酸还原酶活性作为主要的酶活性，这表明寄生虫的线粒体呼吸系统高度适应厌氧环境。高效液相色谱-质谱分析表明，寄生虫线粒体的主要醌是Rhodoquinone-10，它通常被其他真核生物的NADH-延胡索酸还原酶系统用作无氧呼吸的电子介质。这也提示E.多室原蜱具有厌氧呼吸链，其中寄生虫的复合物11起着罗多喹啉-延胡索酸还原酶的作用。此外，使用呼吸链抑制剂对线粒体复合物I的NADH-醌还原酶活性的体外治疗试验表明，它们具有杀死原核生物的有效能力。这些结果表明，寄生虫的线粒体呼吸链是一个很有前途的目标化疗泡球蚴病。
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 11 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.