靶向线粒体心磷脂和细胞色素c/心磷脂复合物以促进电子传递并优化线粒体ATP合成。
Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis.
作者信息
Birk A V, Chao W M, Bracken C, Warren J D, Szeto H H
机构信息
Department of Pharmacology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY, USA.
出版信息
Br J Pharmacol. 2014 Apr;171(8):2017-28. doi: 10.1111/bph.12468.
BACKGROUND AND PURPOSE
Cardiolipin 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 APPROACH
Interactions 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 RESULTS
SS-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 IMPLICATIONS
SS-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.
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疾病有关。细胞色素c与心磷脂之间的疏水相互作用将细胞色素c从电子载体转变为过氧化物酶。除心磷脂过氧化外，这还会阻碍电子通量并抑制线粒体ATP合成。SS - 31（D - Arg - 二甲基Tyr - Lys - Phe - NH2）选择性地结合心磷脂并抑制细胞色素c过氧化物酶活性。在此，我们研究了SS - 31是否也能保护细胞色素c的电子载体功能。
实验方法
使用仅含磷脂酰胆碱或同时含心磷脂的脂质体和双分子层研究SS - 31与心磷脂的相互作用。通过荧光光谱、浊度和核磁共振评估结构相互作用。通过体外细胞色素c还原以及使用线粒体、冷冻和新鲜线粒体的氧气消耗来确定心磷脂对细胞色素c电子转移动力学的影响。
主要结果
SS - 31仅以约1:1的比例与含心磷脂的脂质体和双分子层相互作用。核磁共振研究表明，SS - 31的芳香族残基深入含心磷脂的双层膜。在添加心磷脂的情况下，SS - 31恢复了细胞色素c还原和线粒体氧气消耗。在新鲜线粒体中，SS - 31增加了状态3呼吸和ATP合成效率。
结论与意义
SS - 31选择性地靶向心磷脂并调节其与细胞色素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。这类新型的心磷脂治疗剂有可能恢复线粒体生物能量学，用于治疗多种年龄相关疾病。
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