Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species.

TitleInactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species.
Publication TypeJournal Article
Year of Publication2012
AuthorsHurd, TR, Collins, Y, Abakumova, I, Chouchani, ET, Baranowski, B, Fearnley, IM, Prime, TA, Murphy, MP, James, AM
JournalJ Biol Chem
Date Published2012 Oct 12
KeywordsAdenosine Triphosphate, Animals, Citric Acid Cycle, HEK293 Cells, Humans, Hydrogen Peroxide, Mitochondria, Heart, Mitochondrial Proteins, Protein-Serine-Threonine Kinases, Pyruvate Dehydrogenase Complex, Rats, Signal Transduction, Superoxides

Reactive oxygen species are byproducts of mitochondrial respiration and thus potential regulators of mitochondrial function. Pyruvate dehydrogenase kinase 2 (PDHK2) inhibits the pyruvate dehydrogenase complex, thereby regulating entry of carbohydrates into the tricarboxylic acid (TCA) cycle. Here we show that PDHK2 activity is inhibited by low levels of hydrogen peroxide (H(2)O(2)) generated by the respiratory chain. This occurs via reversible oxidation of cysteine residues 45 and 392 on PDHK2 and results in increased pyruvate dehydrogenase complex activity. H(2)O(2) derives from superoxide (O(2)(.)), and we show that conditions that inhibit PDHK2 also inactivate the TCA cycle enzyme, aconitase. These findings suggest that under conditions of high mitochondrial O(2)(.) production, such as may occur under nutrient excess and low ATP demand, the increase in O(2)() and H(2)O(2) may provide feedback signals to modulate mitochondrial metabolism.

Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M112.400002
PubMed ID22910903
PubMed Central IDPMC3471752
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom