Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis
Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis
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DOI：
10.1111/bph.12468
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发表时间：
2014-04-01
影响因子：
7.3
通讯作者：
Szeto, H. H.
中科院分区：
文献类型：
--
作者：
Birk, A. V.;Chao, W. M.;Szeto, H. H.
背景与目的心磷脂在线粒体呼吸中起重要作用，心磷脂过氧化与年龄相关性疾病有关。细胞色素c和心磷脂之间的疏水相互作用将细胞色素c从电子载体转化为过氧化物酶。除了心磷脂过氧化作用外，这还阻碍电子通量并抑制线粒体ATP合成。SS-31（D-Arg-dimethylTyr-Lys-Phe-NH 2）选择性结合心磷脂并抑制细胞色素c过氧化物酶活性。在这里，我们研究了SS-31是否也保护细胞色素c.Experimental ApproachInteractions的SS-31与心磷脂的电子载体功能进行了研究，使用脂质体和双胞含有磷脂酰胆碱单独或与心磷脂。通过荧光光谱、浊度和核磁共振评估结构相互作用。心磷脂对细胞色素c的电子传递动力学的影响进行了测定细胞色素c在体外的还原和氧消耗使用mitoplasts，冷冻和新鲜mitochondrial.Key ResultsSS-31相互作用只与脂质体和bicelles含有心磷脂在约1：1的比例。NMR研究表明，SS-31的芳香族残基渗透到含心磷脂的双层中。SS-31恢复细胞色素c还原和线粒体耗氧量在添加心磷脂的存在下。在新鲜的线粒体，SS-31增加状态3呼吸和ATP synthesized.Conclusions和ImplicationsSS-31的效率选择性地针对心磷脂和调制其与细胞色素c的相互作用。SS-31抑制细胞色素c/心磷脂复合物过氧化物酶活性，同时保护其作为电子载体的能力，从而优化线粒体电子传递和ATP合成。这类新的心磷脂疗法有可能恢复线粒体生物能量学，用于治疗许多与年龄有关的疾病。链接文章这篇文章是线粒体药理学主题问题的一部分：能量，损伤及超越。要查看本期的其他文章，请访问
Background and PurposeCardiolipin plays an important role in mitochondrial respiration and cardiolipin peroxidation is associated with age-related diseases. Hydrophobic interactions between cytochrome c and cardiolipin converts cytochrome c from an electron carrier to a peroxidase. In addition to cardiolipin peroxidation, this impedes electron flux and inhibits mitochondrial ATP synthesis. SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH2) selectively binds to cardiolipin and inhibits cytochrome c peroxidase activity. Here, we examined whether SS-31 also protected the electron carrier function of cytochrome c.Experimental ApproachInteractions of SS-31 with cardiolipin were studied using liposomes and bicelles containing phosphatidylcholine alone or with cardiolipin. Structural interactions were assessed by fluorescence spectroscopy, turbidity and nuclear magnetic resonance. Effects of cardiolipin on electron transfer kinetics of cytochrome c were determined by cytochrome c reduction in vitro and oxygen consumption using mitoplasts, frozen and fresh mitochondria.Key ResultsSS-31 interacted only with liposomes and bicelles containing cardiolipin in about 1:1 ratio. NMR studies demonstrated that the aromatic residues of SS-31 penetrated deep into cardiolipin-containing bilayers. SS-31 restored cytochrome c reduction and mitochondrial oxygen consumption in the presence of added cardiolipin. In fresh mitochondria, SS-31 increased state 3 respiration and efficiency of ATP synthesis.Conclusions and ImplicationsSS-31 selectively targeted cardiolipin and modulated its interaction with cytochrome c. SS-31 inhibited the cytochrome c/cardiolipin complex peroxidase activity while protecting its ability to serve as an electron carrier, thus optimizing mitochondrial electron transport and ATP synthesis. This novel class of cardiolipin therapeutics has the potential to restore mitochondrial bioenergetics for treatment of numerous age-related diseases.Linked ArticlesThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit