Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines
Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines
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DOI：
10.1016/j.bcp.2005.08.022
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发表时间：
2005-12-05
影响因子：
5.8
通讯作者：
Szeto, HH
中科院分区：
文献类型：
--
作者：
Zhao, KS;Luo, GX;Szeto, HH
氧化应激和线粒体氧化损伤与衰老和许多常见疾病有关。线粒体是细胞中活性氧（ROS）的主要来源，特别容易受到氧化损伤。线粒体氧化损伤导致线粒体通透性转变（MPT）、线粒体去极化、ROS进一步产生、肿胀和细胞色素c （cyt c）的释放。胞浆cyt c通过激活caspase级联触发细胞凋亡。在目前的工作中，我们研究了一种新的细胞穿透性线粒体靶向肽抗氧化剂在两种神经细胞系中保护氧化诱导的线粒体功能障碍和凋亡的能力。叔丁基过氧化氢（thbhp）处理24小时可导致N(2)A和SH-SY5Y细胞的脂质过氧化和细胞凋亡，并伴有磷脂酰丝氨酸易位、核浓缩和caspase活性增加。用三必和必拓处理的细胞显示细胞内ROS显著增加，线粒体去极化和线粒体活力降低。同时给予< 1 nM SS-31 （d - arg -Dmt- lys - ph - nh2; Dmt = 2′，6′二甲基酪氨酸）显著降低细胞内ROS，增加线粒体电位，并阻止bhp诱导的细胞凋亡。SS-31的显著效力可以通过其广泛的细胞摄取和选择性分配到线粒体来解释。细胞内[H-3]SS-31浓度比细胞外浓度高6倍。使用分离的线粒体进行的研究表明，[H-3]SS-31在线粒体颗粒中的浓度接近5000倍。通过集中在线粒体内膜，SS-31定位于ROS产生的部位，因此可以防止线粒体氧化损伤和进一步的ROS产生。SS-31代表了线粒体靶向抗氧化剂的新平台，具有广泛的治疗潜力。(c) 2005爱思唯尔公司版权所有。
Oxidative stress and mitochondrial oxidative damage have been implicated in aging and many common diseases. Mitochondria are a primary source of reactive oxygen species (ROS) in the cell, and are particularly susceptible to oxidative damage. Oxidative damage to mitochondria results in mitochondrial permeability transition (MPT), mitochondrial depolarization, further ROS production, swelling, and release of cytochrome c (cyt c). Cytosolic cyt c triggers apoptosis by activating the caspase cascade. In the present work, we examined the ability of a novel cell-penetrating, mitochondria-targeted peptide antioxidant in protecting against oxidant-induced mitochondrial dysfunction and apoptosis in two neuronal cell lines. Treatment with tert-butyl hydroperoxide (tBHP) for 24 h resulted in lipid peroxidation and significant cell death via apoptosis in both N(2)A and SH-SY5Y cells, with phosphatidylserine translocation, nuclear condensation and increased caspase activity. Cells treated with tBHP showed significant increase in intracellular ROS, mitochondrial depolarization and reduced mitochondrial viability. Concurrent treatment with < 1 nM SS-31 (D-Arg-Dmt-Lys-Phe-NH2; Dmt = 2',6'dimethyltyrosine) significantly decreased intracellular ROS, increased mitochondrial potential, and prevented tBHP-induced apoptosis. The remarkable potency of SS-31 can be explained by its extensive cellular uptake and selective partitioning into mitochondria. Intracellular concentrations of [H-3]SS-31 were 6-fold higher than extracellular concentrations. Studies using isolated mitochondria revealed that [H-3]SS-31 was concentrated similar to 5000-fold in the mitochondrial pellet. By concentrating in the inner mitochondrial membrane, SS-31 is localized to the site of ROS production, and can therefore protect against mitochondrial oxidative damage and further ROS production. SS-31 represents a novel platform of mitochondria-targeted antioxidants with broad therapeutic potential. (c) 2005 Elsevier Inc. All rights reserved.