Recent research on respiratory chain of the parasitic helminth, Ascaris suum has shown that the mitochondrial
NADH-fumarate reductase system (
fumarate respiration), which is composed of complex I (
NADH-
rhodoquinone reductase),
rhodoquinone and complex II (rhodoquinol-
fumarate reductase) plays an important role in the anaerobic energy metabolism of adult parasites inhabiting hosts. The
enzymes in these parasite-specific pathways are potential target for
chemotherapy. We isolated a novel compound,
nafuredin, from Aspergillus niger, which inhibits
NADH-fumarate reductase in helminth mitochondria at nM order. It competes for the
quinone-binding site in complex I and shows high selective toxicity to the helminth
enzyme. Moreover,
nafuredin exerts
anthelmintic activity against Haemonchus contortus in in vivo trials with sheep indicating that mitochondrial complex I is a promising target for
chemotherapy. In addition to complex I, complex II is a good target because its catalytic direction is reverse of
succinate-ubiquionone
reductase in the host complex II. Furthermore, we found atpenin and
flutolanil strongly and specifically inhibit mitochondrial complex II. Interestingly,
fumarate respiration was found not only in the parasites but also in some types of human
cancer cells. Analysis of the mitochondria from the
cancer cells identified an anthelminthic as a specific inhibitor of the
fumarate respiration. Role of
isoforms of human complex II in the hypoxic condition of
cancer cells and fetal tissues is a challenge. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010.