Enzymes in the mitochondrial respiratory chain are involved in various physiological events in addition to their essential role in the production of ATP by oxidative phosphorylation. The use of specific and potent inhibitors of complex I (NADH-ubiquinone reductase) and complex III (ubiquinol-cytochrome c reductase), such as rotenone and antimycin, respectively, has allowed determination of the role of these enzymes in physiological processes. However, unlike complexes I, III, and IV (cytochrome c oxidase), there are few potent and specific inhibitors of complex II (succinate-ubiquinone reductase) that have been described. In this article, we report that atpenins potently and specifically inhibit the succinate-ubiquinone reductase activity of mitochondrial complex II. Therefore, atpenins may be useful tools for clarifying the biochemical and structural properties of complex II, as well as for determining its physiological roles in mammalian tissues. T he use of specific and potent inhibitors of respiration has enabled the investigation of how the respiratory enzymes function in physiological processes. However, unlike other enzyme complexes in the respiratory chain, there has been a lack of potent and specific inhibitors of complex II [succinateubiquinone reductase (SQR)]. Although carboxin (5,6-dihydro-2-methyl-N-phenyl-1,4-oxathiin-3-carboxamide), TTFA [4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione], and HQNO (2-heptyl-4-hydroxyquinoline N-oxide) have long been known as complex II inhibitors and have been used extensively to elucidate the structure-function relationships of complex II, rather higher concentration is required for the inhibition (1). This result has hampered the study of the structure-function relationship of the complex II enzyme, as well as its roles in physiological processes.Complex II catalyzes the oxidation of succinate in the inner membrane of mitochondria and in the cytoplasmic membrane of bacteria (1-3). In addition to its function as a dehydrogenase in the respiratory system, complex II plays an important role in the tricarboxylic acid cycle. Mitochondrial complex II is an integral membrane protein consisting of four subunits (Fig. 1). The largest subunit is the 70-kDa, FAD-containing flavoprotein subunit (Fp). The dehydrogenase catalytic portion of complex II is formed by Fp and an Ϸ30-kDa iron-sulfur protein subunit (Ip) containing three different types of iron-sulfur clusters. The small hydrophobic subunits, SDHC or CybL (Ϸ15 kDa) and SDHD or CybS (Ϸ13 kDa), anchor the catalytic portion to the membrane and are also required for electron transfer to quinones. In contrast to mitochondrial complex IIs, some bacterial complex IIs contain only one larger hydrophobic polypeptide as a membrane anchor (see ref. 4 for reviews).In addition to its essential role in energy production, various recent findings suggest that mutant variants of complex II are involved in causing diverse physiological disorders. For instance, a mutation in the CybL subunit in Caenorhabditis elegans (mev-1 mutant) resu...

In the course of our screening program to discover antimalarial antibiotics, which are active against drug resistant Plasmodium falciparum in vitro and rodents infected with P. berghei in vivo, from the culture broth of microorganisms, we found a selective and potent active substance produced by an actinomycete strain K99-0413. It was identified as a known polyether antibiotic, X-206. We also compared the in vitro antimalarial activities and cytotoxicities of 12 known polyethers with X-206. Amongthem, X-206 showed the most selective and potent inhibitory effect against both drug resistant and sensitive strains of P.

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