For COVID-19 vaccine updates, please review our information guide. For patient eligibility and scheduling availability, please visit VaccineTogetherNY.org.

Production of superoxide/H2O2 by dihydroorotate dehydrogenase in rat skeletal muscle mitochondria.

TitleProduction of superoxide/H2O2 by dihydroorotate dehydrogenase in rat skeletal muscle mitochondria.
Publication TypeJournal Article
Year of Publication2014
AuthorsHey-Mogensen M, Goncalves RLS, Orr AL, Brand MD
JournalFree Radic Biol Med
Volume72
Pagination149-55
Date Published2014 Jul
ISSN1873-4596
KeywordsAnimals, Female, Hydrogen Peroxide, Mitochondria, Muscle, Muscle, Skeletal, Oxidoreductases Acting on CH-CH Group Donors, Rats, Rats, Wistar, Superoxides
Abstract

Dehydrogenases that use ubiquinone as an electron acceptor, including complex I of the respiratory chain, complex II, and glycerol-3-phosphate dehydrogenase, are known to be direct generators of superoxide and/or H2O2. Dihydroorotate dehydrogenase oxidizes dihydroorotate to orotate and reduces ubiquinone to ubiquinol during pyrimidine metabolism, but it is unclear whether it produces superoxide and/or H2O2 directly or does so only indirectly from other sites in the electron transport chain. Using mitochondria isolated from rat skeletal muscle we establish that dihydroorotate oxidation leads to superoxide/H2O2 production at a fairly high rate of about 300pmol H2O2·min(-1)·mg protein(-1) when oxidation of ubiquinol is prevented and complex II is uninhibited. This H2O2 production is abolished by brequinar or leflunomide, known inhibitors of dihydroorotate dehydrogenase. Eighty percent of this rate is indirect, originating from site IIF of complex II, because it can be prevented by malonate or atpenin A5, inhibitors of complex II. In the presence of inhibitors of all known sites of superoxide/H2O2 production (rotenone to inhibit sites in complex I (site IQ and, indirectly, site IF), myxothiazol to inhibit site IIIQo in complex III, and malonate plus atpenin A5 to inhibit site IIF in complex II), dihydroorotate dehydrogenase generates superoxide/H2O2, at a small but significant rate (23pmol H2O2·min(-1)·mg protein(-1)), from the ubiquinone-binding site. We conclude that dihydroorotate dehydrogenase can generate superoxide and/or H2O2 directly at low rates and is also capable of indirect production at higher rates from other sites through its ability to reduce the ubiquinone pool.

DOI10.1016/j.freeradbiomed.2014.04.007
Alternate JournalFree Radic. Biol. Med.
PubMed ID24746616