Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration.
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.
Anderson
Ethan J
EJ
John B. Pierce Laboratory and Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06519, USA.
Yamazaki
Hanae
H
Neufer
P Darrell
PD
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D019069:Cell Respiration / Q000502:physiology*; D005215:Fasting; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000737:chemistry* / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000502:physiology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D019308:Palmitic Acid / Q000494:pharmacology; D010805:Physical Conditioning, Animal; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019802:Succinic Acid / Q000494:pharmacology; D013997:Time Factors; D000071247:Uncoupling Protein 3
D001786:Blood Glucose; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D019308:Palmitic Acid; D019802:Succinic Acid; D006861:Hydrogen Peroxide