Mitoparan and target-selective chimeric analogues: Membrane translocation and intracellular redistribution induces mitochondrial apoptosis
Mitoparan and target-selective chimeric analogues: Membrane translocation and intracellular redistribution induces mitochondrial apoptosis
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DOI：
10.1016/j.bbamcr.2008.01.009
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发表时间：
2008-05-01
影响因子：
5.1
通讯作者：
Howl, John
中科院分区：
文献类型：
--
作者：
Jones, Sarah;Martel, Cecile;Howl, John
Mastoparan和结构相关的两性肽可通过增强坏死和/或凋亡途径诱导细胞死亡。为了更精确地描述细胞毒性机制，我们确定[Lys(5,8) Aib(10)]mastoparan （mitoparan）通过核酸内切酶和caspase-3激活以及磷脂酰丝氨酸易位特异性诱导U373MG和ECV304细胞凋亡。活细胞成像证实，在质膜易位后，线粒体特异性地与线粒体共定位。补充研究表明，mitoparan通过与通透性过渡孔复合物VDAC的蛋白合作，诱导离体线粒体的肿胀和通透性，导致凋亡因子细胞色素c的释放。mitoparan的n端酰化促进了嵌合肽的合成，这些嵌合肽包含靶向性地址基序，包括整合素特异性RGD序列和Fas配体模拟物。值得注意的是，这些有心理组织的肽进一步增强了细胞毒性。我们认为，mitoparan及其嵌合类似物的细胞渗透性、线粒体毒性和致凋亡特性为细胞凋亡的研究和治疗诱导提供了新的见解。(C) 2008 Elsevier B.V.版权所有
Mastoparan, and structurally-related amphipathic peptides, may induce cell death by augmentation of necrotic and/or apoptotic pathways. To more precisely delineate cytotoxic mechanisms, we determined that [Lys(5,8) Aib(10)]mastoparan (mitoparan) specifically induces apoptosis of U373MG and ECV304 cells, as demonstrated by endonuclease and caspase-3 activation and phosphatidylserine translocation. Live cell imaging confirmed that, following translocation of the plasma membrane, mitoparan specifically co-localizes with mitochondria. Complementary studies indicated that mitoparan induces swelling and permeabilization of isolated mitochondria, through cooperation with a protein of the permeability transition pore complex VDAC, leading to the release of the apoptogenic factor, cytochrome c. N-terminal acylation of mitoparan facilitated the synthesis of chimeric peptides that incorporated target-specific address motifs including an integrin-specific RGD sequence and a Fas ligand mimetic. Significantly, these sychnologically-organised peptides demonstrated further enhanced cytotoxic potencies. We conclude that the cell penetrant, mitochondriotoxic and apoptogenic properties of mitoparan, and its chimeric analogues, offer new insights to the study and therapeutic induction of apoptosis. (C) 2008 Elsevier B.V. All rights reserved.