Abstract：
The selective interaction of cytochrome c (Cyt c) with cardiolipin (CL) is involved in mitochondrial membrane permeabilization, an essential step for the release of apoptosis activators. The structural basis and modulatory mechanism are, however, poorly understood. Here, we report that Cyt c can induce CL peroxidation independent of reactive oxygen species, which is controlled by its redox states. The structural basis of the Cyt c-CL binding was unveiled by comprehensive spectroscopic investigation and mass spectrometry. The Cyt c-induced permeabilization and its effect on membrane collapse, pore formation, and budding are observed by confocal microscopy. Moreover, cytochrome c oxidase dysfunction is found to be associated with the initiation of Cyt c redox-controlled membrane permeabilization. These results verify the significance of a redox-dependent modulation mechanism at the early stage of apoptosis, which can be exploited for the design of cytochrome c oxidase-targeted apoptotic inducers in cancer therapy.
摘要：
细胞色素c（Cytc）与心磷脂（CL）的选择性相互作用参与线粒体膜透化，释放凋亡激活剂的重要步骤。结构基础和调节机制是，然而,知之甚少。这里,我们报道，Cytc可以诱导CL过氧化反应，而与活性氧无关，由其氧化还原状态控制。通过全面的光谱研究和质谱法揭示了Cytc-CL结合的结构基础。Cytc诱导的透化作用及其对膜塌陷的影响，孔隙形成,通过共聚焦显微镜观察出芽。此外，发现细胞色素c氧化酶功能障碍与Cytc氧化还原控制的膜透化作用的启动有关。这些结果验证了细胞凋亡早期氧化还原依赖性调节机制的意义。可用于癌症治疗中细胞色素c氧化酶靶向凋亡诱导剂的设计。
