Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration
Induction of endogenous uncoupling protein 3 suppresses mitochondrial oxidant emission during fatty acid-supported respiration
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DOI：
10.1074/jbc.m706129200
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发表时间：
2007-10-26
影响因子：
4.8
通讯作者：
Neufer, P. Darrell
中科院分区：
文献类型：
--
作者：
Anderson, Ethan J.;Yamazaki, Hanae;Neufer, P. Darrell
解偶联蛋白3 （Uncoupling protein 3, UCP3）在骨骼肌中与脂质代谢升高相关的代谢状态下表达显著增加，但UCP3在生理背景下的功能仍存在争议。这里，在单次运动加18小时的恢复（Ex/R）后，大鼠和小鼠（野生型）腓肠肌制备的渗透性纤维束中，原位测量了线粒体H2O2排放和呼吸，诱导了类似的2-4倍的UCP3蛋白增加。在Ex/R纤维中，只有在添加棕榈酸盐（已知的UCP3激活剂）或底物条件下才能明显提高解偶联活性（即在琥珀酸盐或棕榈酰左旋肉碱/苹果酸盐而不是丙酮酸盐/苹果酸盐支持的呼吸作用下），表明UCP3被内源性活性氧激活。在完全缺乏UCP3 （UCP3(-/-)）的小鼠中，Ex/R不能诱导解偶联活性。令人惊讶的是，当UCP3活性被GDP（大鼠）抑制或缺乏UCP3 （UCP3(-/-)）时，与未运动的对照纤维相比，Ex/R中的H2O2排放量显著（p < 0.05）更高。总的来说，这些发现表明，在运动后恢复期间，骨骼肌中线粒体的氧化剂释放电位增加，可能是由于长期依赖脂质代谢和/或线粒体生物化学/形态改变的结果，体内诱导UCP3介导解偶联活性的增加，从而将线粒体H2O2释放恢复到未运动的控制水平。
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 similar to 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.