Uncoupling protein-3 lowers reactive oxygen species production in isolated mitochondria.
Uncoupling protein-3 lowers reactive oxygen species production in isolated mitochondria.
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DOI：
10.1016/j.freeradbiomed.2010.05.010
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发表时间：
2010-08-15
影响因子：
7.4
通讯作者：
Brand, Martin D.
中科院分区：
文献类型：
--
作者：
Toime, Laurence J.;Brand, Martin D.
关键词：
线粒体是活性氧（ROS）的主要细胞生产者，并且线粒体ROS的产生随着质子动力的增加而急剧增加。解偶联蛋白（UCP 1，UCP 2和UCP 3）和腺嘌呤核苷酸移位酶诱导质子泄漏响应外源性添加的脂肪酸，超氧化物或脂质过氧化产物。通过这些蛋白质的“温和解偶联”可以提供负反馈环以降低质子动力并减弱ROS产生。使用野生型和UCP 3 −/−小鼠，我们发现在没有外源性激活剂的情况下，天然UCP 3主动降低了分离的通电骨骼肌线粒体中ROS的产生速率。UCP 3在降低ROS产生方面的估计比活性比腺嘌呤核苷酸移位酶高90至500倍。通过测量UCP 3对ROS产生的影响是否可以通过化学解偶联来模拟来测试温和解偶联假设。一种化学解偶联剂模拟了UCP 3在线粒体凋亡后早期时间点的作用，支持轻度解偶联假说。然而，在稍后的时间点，解偶联剂没有模拟UCP 3，这表明UCP 3也可以通过膜电位非依赖性机制影响ROS的产生。
Mitochondria are the major cellular producers of reactive oxygen species (ROS), and mitochondrial ROS production increases steeply with increased protonmotive force. The uncoupling proteins (UCP1, UCP2 and UCP3) and adenine nucleotide translocase induce proton leak in response to exogenously added fatty acids, superoxide or lipid peroxidation products. “Mild uncoupling” by these proteins may provide a negative feedback loop to decrease protonmotive force and attenuate ROS production. Using wild type and Ucp3−/− mice, we found that native UCP3 actively lowers the rate of ROS production in isolated energized skeletal muscle mitochondria, in the absence of exogenous activators. The estimated specific activity of UCP3 in lowering ROS production was 90 to 500 times higher than that of the adenine nucleotide translocase. The mild uncoupling hypothesis was tested by measuring whether the effect of UCP3 on ROS production could be mimicked by chemical uncoupling. A chemical uncoupler mimicked the effect of UCP3 at early time points after mitochondrial energization, in support of the mild uncoupling hypothesis. However, at later time points the uncoupler did not mimic UCP3, suggesting that UCP3 can also affect on ROS production through a membrane potential-independent mechanism.
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