University of Ottawa, Department of Biochemistry, Microbiology, and Immunology, Ottawa, ON, Canada.
FASEB J. 2012 Jan;26(1):363-75. doi: 10.1096/fj.11-189639. Epub 2011 Sep 22.
Reduced glutathione (GSH) is the major determinant of redox balance in mitochondria and as such is fundamental in the control of cellular bioenergetics. GSH is also the most important nonprotein antioxidant molecule in cells. Surprisingly, the effect of redox environment has never been examined in skeletal muscle and brown adipose tissue (BAT), two tissues that have exceptional dynamic range and that are relevant to the development of obesity and related diseases. Here, we show that the redox environment plays crucial, yet divergent, roles in modulating mitochondrial bioenergetics in skeletal muscle and BAT. Skeletal muscle mitochondria were found to naturally have a highly reduced environment (GSH/GSSG≈46), and this was associated with fairly high (∼40%) rates of state 4 (nonphosphorylating) respiration and decreased reactive oxygen species (ROS) emission. The deglutathionylation of uncoupling protein 3 (UCP3) following an increase in the reductive potential of mitochondria results in a further increase in nonphosphorylating respiration (∼20% in situ). BAT mitochondria were found to have a much more oxidized status (GSH/GSSG≈13) and had basal reactive oxygen species emission that was higher (∼250% increase in ROS generation) than that in skeletal muscle mitochondria. When redox status was subsequently increased (i.e., more reduced), UCP1-mediated uncoupling was more sensitive to GDP inhibition. Surprisingly, BAT was found to be devoid of glutaredoxin-2 (Grx2) expression, while there was abundant expression in skeletal muscle. Taken together, these findings reveal the importance of redox environment in controlling bioenergetic functions in both tissues, and the highly unique characteristics of BAT in this regard.
还原型谷胱甘肽（GSH）是线粒体氧化还原平衡的主要决定因素，因此是控制细胞生物能量学的基础。GSH 也是细胞中最重要的非蛋白抗氧化分子。令人惊讶的是，氧化还原环境对骨骼肌和棕色脂肪组织（BAT）的影响从未被研究过，这两种组织具有特殊的动态范围，与肥胖和相关疾病的发展有关。在这里，我们表明氧化还原环境在调节骨骼肌和 BAT 中线粒体生物能量学方面起着至关重要但不同的作用。发现骨骼肌线粒体自然具有高度还原的环境（GSH/GSSG≈46），这与相当高（约 40%）的状态 4（非磷酸化）呼吸率和减少的活性氧物种（ROS）排放有关。解偶联蛋白 3（UCP3）的去谷胱甘肽化后，线粒体的还原电位增加，导致非磷酸化呼吸进一步增加（原位增加约 20%）。BAT 线粒体的氧化状态要高得多（GSH/GSSG≈13），并且基础活性氧物种的排放也更高（ROS 生成增加约 250%）比骨骼肌线粒体。随后，当氧化还原状态增加（即更还原）时，UCP1 介导的解偶联对 GDP 抑制更为敏感。令人惊讶的是，BAT 中发现缺乏谷胱甘肽还原酶-2（Grx2）的表达，而骨骼肌中则有丰富的表达。综上所述，这些发现揭示了氧化还原环境在控制两种组织生物能量学功能中的重要性，以及 BAT 在这方面的高度独特特征。
