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J. Biol. Chem., Vol. 282, Issue 43, 31257-31266, October 26, 2007

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Induction of Endogenous Uncoupling Protein 3 Suppresses Mitochondrial Oxidant Emission during Fatty Acid-supported Respiration^*

Ethan J. Anderson, Hanae Yamazaki, and P. Darrell Neufer¹

From the John B. Pierce Laboratory and Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06519 and Exercise and Sport Science and Physiology, East Carolina University, Greenville, North Carolina 27834

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 H₂O₂ 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 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 H₂O₂ 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^–/–), H₂O₂ 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 H₂O₂ emission to non-exercised, control levels.

Received for publication, July 25, 2007 , and in revised form, August 30, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834. Tel.: 252-744-2780; E-mail: neuferp{at}ecu.edu.

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