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Inhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening.

TitleInhibitors of ROS production by the ubiquinone-binding site of mitochondrial complex I identified by chemical screening.
Publication TypeJournal Article
Year of Publication2013
AuthorsOrr AL, Ashok D, Sarantos MR, Shi T, Hughes RE, Brand MD
JournalFree Radic Biol Med
Volume65
Pagination1047-1059
Date Published2013 Dec
ISSN1873-4596
KeywordsAnimals, Binding Sites, Electron Transport Complex I, Enzyme Inhibitors, Female, High-Throughput Screening Assays, Membrane Potential, Mitochondrial, Mitochondria, Muscle, Oxidation-Reduction, Rats, Wistar, Reactive Oxygen Species, Ubiquinone
Abstract

Mitochondrial production of reactive oxygen species is often considered an unavoidable consequence of aerobic metabolism and currently cannot be manipulated without perturbing oxidative phosphorylation. Antioxidants are widely used to suppress effects of reactive oxygen species after formation, but they can never fully prevent immediate effects at the sites of production. To identify site-selective inhibitors of mitochondrial superoxide/H2O2 production that do not interfere with mitochondrial energy metabolism, we developed a robust small-molecule screen and secondary profiling strategy. We describe the discovery and characterization of a compound (N-cyclohexyl-4-(4-nitrophenoxy)benzenesulfonamide; CN-POBS) that selectively inhibits superoxide/H2O2 production from the ubiquinone-binding site of complex I (site I(Q)) with no effects on superoxide/H2O2 production from other sites or on oxidative phosphorylation. Structure/activity studies identified a core structure that is important for potency and selectivity for site I(Q). By employing CN-POBS in mitochondria respiring on NADH-generating substrates, we show that site I(Q) does not produce significant amounts of superoxide/H2O2 during forward electron transport on glutamate plus malate. Our screening platform promises to facilitate further discovery of direct modulators of mitochondrially derived oxidative damage and advance our ability to understand and manipulate mitochondrial reactive oxygen species production under both normal and pathological conditions.

DOI10.1016/j.freeradbiomed.2013.08.170
Alternate JournalFree Radic. Biol. Med.
PubMed ID23994103
PubMed Central IDPMC4321955
Grant ListTL1AG032116 / AG / NIA NIH HHS / United States
RL1 GM084432 / GM / NIGMS NIH HHS / United States
TL1 AG032116 / AG / NIA NIH HHS / United States
R01 AG033542 / AG / NIA NIH HHS / United States
R01AG033542 / AG / NIA NIH HHS / United States
RL1GM084432 / GM / NIGMS NIH HHS / United States