Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species.
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.
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, United Kingdom.
Thomas R
TR
Hurd
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, United Kingdom.
Yvonne
Y
Collins
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, United Kingdom.
Irina
I
Abakumova
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, United Kingdom.
Edward T
ET
Chouchani
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, United Kingdom.
Bartlomiej
B
Baranowski
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, United Kingdom.
Ian M
IM
Fearnley
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, United Kingdom.
Tracy A
TA
Prime
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, United Kingdom. Electronic address: mpm@mrc-mbu.cam.ac.uk.
Michael P
MP
Murphy
Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, United Kingdom.
Andrew M
AM
James
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002952:Citric Acid Cycle / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*
D024101:Mitochondrial Proteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D013481:Superoxides; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases