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Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration

J Biol Chem. 2007 Oct 26;282(43):31257-66. doi: 10.1074/jbc.M706129200. Epub 2007 Aug 30.

Abstract

Uncoupling protein 3 (UCP3) expression increases dramatically in skeletal muscle under metabolic states associated with elevated lipid metabolism, yet the function of UCP3 in a physiological context remains controversial. Here, in situ mitochondrial H(2)O(2) emission and respiration were measured in permeabilized fiber bundles prepared from both rat and mouse (wild-type) gastrocnemius muscle after a single bout of exercise plus 18 h of recovery (Ex/R) that induced a approximately 2-4-fold increase in UCP3 protein. Elevated uncoupling activity (i.e. GDP inhibitable) was evident in Ex/R fibers only upon the addition of palmitate (known activator of UCP3) or under substrate conditions eliciting substantial rates of H(2)O(2) production (i.e. respiration supported by succinate or palmitoyl-L-carnitine/malate but not pyruvate/malate), indicative of UCP3 activation by endogenous reactive oxygen species. In mice completely lacking UCP3 (ucp3(-/-)), Ex/R failed to induce uncoupling activity. Surprisingly, when UCP3 activity was inhibited by GDP (rats) or in the absence of UCP3 (ucp3(-/-)), H(2)O(2) emission was significantly (p < 0.05) higher in Ex/R versus non-exercised control fibers. Collectively, these findings demonstrate that the oxidant emitting potential of mitochondria is increased in skeletal muscle during recovery from exercise, possibly as a consequence of prolonged reliance on lipid metabolism and/or altered mitochondrial biochemistry/morphology and that induction of UCP3 in vivo mediates an increase in uncoupling activity that restores mitochondrial H(2)O(2) emission to non-exercised, control levels.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Cell Respiration / physiology*
  • Fasting
  • Fatty Acids / blood
  • Fatty Acids / metabolism*
  • Hydrogen Peroxide / metabolism
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria / chemistry*
  • Mitochondria / metabolism*
  • Mitochondria, Muscle / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Muscle, Skeletal / physiology
  • Oxidation-Reduction
  • Oxygen Consumption
  • Palmitic Acid / pharmacology
  • Physical Conditioning, Animal
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Succinic Acid / pharmacology
  • Time Factors
  • Uncoupling Protein 3

Substances

  • Blood Glucose
  • Fatty Acids
  • Ion Channels
  • Mitochondrial Proteins
  • RNA, Messenger
  • Ucp3 protein, mouse
  • Ucp3 protein, rat
  • Uncoupling Protein 3
  • Palmitic Acid
  • Succinic Acid
  • Hydrogen Peroxide