Molecular Bioenergetics Group, Cluster of Excellence Frankfurt "Macromolecular Complexes," Medical School, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Mol Pharmacol. 2011 May;79(5):814-22. doi: 10.1124/mol.110.070342. Epub 2011 Jan 28.
In this study, we have analyzed the effect of different cardioprotective complex II inhibitors on the mitochondrial production of reactive oxygen species (ROS) because ROS seem to be essential for signaling during preconditioning to prevent ischemia/reperfusion injury. Despite different binding sites and concentrations required for half-maximal inhibition-ranging from nanomolar for the Q site inhibitor atpenin A5 to millimolar for the succinate analog malonate-all inhibitors modulated ROS production in the same ambivalent fashion: they promoted the generation of superoxide at the Q(o) site of complex III under conditions of "oxidant-induced reduction" but attenuated ROS generated at complex I due to reverse electron transfer. All inhibitors showed these ambivalent effects independent of the presence of K(+). These findings suggest a direct modulation of mitochondrial ROS generation during cardioprotection via complex II inhibition and question the recently proposed role of complex II as a regulatory component of the putative mitochondrial K(ATP) channel.
在这项研究中，我们分析了不同的心脏保护复合物 II 抑制剂对线粒体产生活性氧物种 (ROS) 的影响，因为 ROS 似乎是预处理过程中信号传导所必需的，以防止缺血/再灌注损伤。尽管需要不同的结合位点和半最大抑制所需的浓度——从 Q 位点抑制剂 atpenin A5 的纳摩尔到琥珀酸类似物丙二酸盐的毫摩尔——所有抑制剂都以相同的矛盾方式调节 ROS 的产生：它们在“氧化还原诱导”条件下促进复合物 III 的 Q(o) 位点的超氧化物生成，但由于反向电子转移而减弱由于复合物 I 产生的 ROS。所有抑制剂都表现出这些矛盾的作用，与 K(+) 的存在无关。这些发现表明，通过复合物 II 抑制对心脏保护过程中线粒体 ROS 的产生进行直接调节，并对最近提出的复合物 II 作为假定的线粒体 K(ATP) 通道的调节成分的作用提出质疑。
