Anaerobic NADH-fumarate reductase system is predominant in the respiratory chain of Echinococcus multilocularis, providing a novel target for the chemotherapy of alveolar echinococcosis.
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.
Matsumoto
Jun
J
Laboratory of Parasitology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Sakamoto
Kimitoshi
K
Shinjyo
Noriko
N
Kido
Yasutoshi
Y
Yamamoto
Nao
N
Yagi
Kinpei
K
Miyoshi
Hideto
H
Nonaka
Nariaki
N
Katakura
Ken
K
Kita
Kiyoshi
K
Oku
Yuzaburo
Y
D000693:Anaerobiosis; D000818:Animals; D004444:Echinococcosis, Hepatic / Q000188:drug therapy; D048210:Echinococcus multilocularis / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D004579:Electron Transport / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology; D009574:Nitro Compounds; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D012402:Rotenone / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D009574:Nitro Compounds; D011799:Quinazolines; D013844:Thiazoles; D012402:Rotenone; D014451:Ubiquinone; D044925:Oxidoreductases Acting on CH-CH Group Donors; C020155:fumarate reductase (NADH); C003304:rhodoquinone; C041747:nitazoxanide