Skulachev Vladimir P, Antonenko Yury N, Cherepanov Dmitry A, Chernyak Boris V, Izyumov Denis S, Khailova Ludmila S, Klishin Sergey S, Korshunova Galina A, Lyamzaev Konstantin G, Pletjushkina Olga Yu, Roginsky Vitaly A, Rokitskaya Tatiana I, Severin Fedor F, Severina Inna I, Simonyan Ruben A, Skulachev Maxim V, Sumbatyan Natalia V, Sukhanova Evgeniya I, Tashlitsky Vadim N, Trendeleva Tatyana A, Vyssokikh Mikhail Yu, Zvyagilskaya Renata A
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Vorobyevy Gory 1, Moscow 119991, Russia.
Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):878-89. doi: 10.1016/j.bbabio.2010.03.015. Epub 2010 Mar 20.
The present state of the art in studies on the mechanisms of antioxidant activities of mitochondria-targeted cationic plastoquinone derivatives (SkQs) is reviewed. Our experiments showed that these compounds can operate as antioxidants in two quite different ways, i.e. (i) by preventing peroxidation of cardiolipin [Antonenko et al., Biochemistry (Moscow) 73 (2008) 1273-1287] and (ii) by fatty acid cycling resulting in mild uncoupling that inhibits the formation of reactive oxygen species (ROS) in mitochondrial State 4 [Severin et al. Proc. Natl. Acad. Sci. USA 107 (2009), 663-668]. The quinol and cationic moieties of SkQ are involved in cases (i) and (ii), respectively. In case (i) SkQH2 interrupts propagation of chain reactions involved in peroxidation of unsaturated fatty acid residues in cardiolipin, the formed SkQ- being reduced back to SkQH2 by heme bH of complex III in an antimycin-sensitive way. Molecular dynamics simulation showed that there are two stable conformations of SkQ1 with the quinol residue localized near peroxyl radicals at C9 or C13 of the linoleate residue in cardiolipin. In mechanism (ii), fatty acid cycling mediated by the cationic SkQ moiety is involved. It consists of (a) transmembrane movement of the fatty acid anion/SkQ cation pair and (b) back flows of free SkQ cation and protonated fatty acid. The cycling results in a protonophorous effect that was demonstrated in planar phospholipid membranes and liposomes. In mitochondria, the cycling gives rise to mild uncoupling, thereby decreasing membrane potential and ROS generation coupled to reverse electron transport in the respiratory chain. In yeast cells, dodecyltriphenylphosphonium (capital ES, Cyrillic12TPP), the cationic part of SkQ1, induces uncoupling that is mitochondria-targeted since capital ES, Cyrillic12TPP is specifically accumulated in mitochondria and increases the H+ conductance of their inner membrane. The conductance of the outer cell membrane is not affected by capital ES, Cyrillic12TPP.
本文综述了线粒体靶向阳离子型质体醌衍生物（SkQs）抗氧化活性机制的研究现状。我们的实验表明，这些化合物可通过两种截然不同的方式发挥抗氧化作用，即：（i）通过防止心磷脂过氧化[Antonenko等人，《生物化学（莫斯科）》73（2008）1273 - 1287]；（ii）通过脂肪酸循环导致轻度解偶联，从而抑制线粒体状态4下活性氧（ROS）的形成[Severin等人，《美国国家科学院院刊》107（2009），663 - 668]。SkQ的氢醌和阳离子部分分别参与情况（i）和（ii）。在情况（i）中，SkQH2中断了心磷脂中不饱和脂肪酸残基过氧化所涉及的链反应的传播，形成的SkQ - 被复合物III的血红素bH以抗霉素敏感的方式还原回SkQH2。分子动力学模拟表明，SkQ1有两种稳定构象，其氢醌残基位于心磷脂中亚油酸残基的C9或C13处的过氧自由基附近。在机制（ii）中，涉及由阳离子SkQ部分介导的脂肪酸循环。它包括（a）脂肪酸阴离子/SkQ阳离子对的跨膜运动和（b）游离SkQ阳离子和质子化脂肪酸的回流。这种循环导致了质子ophorous效应，这在平面磷脂膜和脂质体中得到了证实。在线粒体中，这种循环导致轻度解偶联，从而降低膜电位以及与呼吸链中逆向电子传递相关的ROS生成。在酵母细胞中，SkQ1的阳离子部分十二烷基三苯基鏻（大写ES，西里尔文12TPP）诱导解偶联，这种解偶联是线粒体靶向的，因为大写ES，西里尔文12TPP特异性地积累在线粒体中并增加其内膜的H + 电导。细胞膜外膜的电导不受大写ES，西里尔文12TPP的影响。
