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


ABSTRACT: 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.

SUBMITTER: Hurd TR 

PROVIDER: S-EPMC3471752 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Hurd Thomas R TR   Collins Yvonne Y   Abakumova Irina I   Chouchani Edward T ET   Baranowski Bartlomiej B   Fearnley Ian M IM   Prime Tracy A TA   Murphy Michael P MP   James Andrew M AM  

The Journal of biological chemistry 20120821 42


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 a  ...[more]

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