Apoptotic interactions of cyctochrome c:: Redox flirting with anionic phospholipids within and outside of mitochondria
Apoptotic interactions of cyctochrome c:: Redox flirting with anionic phospholipids within and outside of mitochondria
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DOI：
10.1016/j.bbabio.2006.03.002
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发表时间：
2006-05-01
影响因子：
4.3
通讯作者：
Kagan, V. E.
中科院分区：
文献类型：
--
作者：
Bayir, H.;Fadeel, B.;Kagan, V. E.
自20世纪20年代早期发现细胞色素c（cyt c）并对其结构和线粒体电子传递功能进行详细表征以来，人们花了70多年的时间才认识到，cyt c通过与几种蛋白质相互作用并形成线粒体，在程序性细胞死亡，凋亡中发挥不同的，而不是不那么普遍的作用。最近，已经发现细胞色素c在细胞凋亡中的另外两个基本功能是通过其与阴离子磷脂的相互作用进行的：线粒体特异性磷脂、心磷脂（CL）和质膜磷脂酰丝氨酸（PS）。细胞凋亡程序的执行伴随着大量和早期的活性氧（ROS）的线粒体产生。由于抗氧化剂的增强保护细胞免于凋亡，ROS的产生被认为不是线粒体解体的无意义的副作用，而是在凋亡中发挥了一些尚未确定的作用。这个难题已经得到解决，通过建立线粒体含有一个池的细胞色素，它与CL相互作用，并作为CL加氧酶。加氧酶在细胞凋亡过程中被激活，利用产生的ROS并导致CL的选择性氧化。氧化的CL是从线粒体释放促凋亡因子到胞质溶胶中所必需的。细胞色素c的这种氧化还原机制比其在形成核糖体和半胱天冬酶激活中的其他公认功能更早实现。在胞质溶胶中，释放的cyt c与另一种阴离子磷脂PS相互作用，并在类似的加氧酶反应中催化其氧化。过氧化PS促进其外化，这对于巨噬细胞识别和清除凋亡细胞至关重要。细胞膜PS氧化的氧化还原催化作用是细胞色素c在细胞凋亡和吞噬过程中重要的氧化还原依赖性功能。因此，细胞色素c作为一种阴离子磷脂特异性加氧酶被激活，并为细胞凋亡的基本阶段的执行所需。本文综述了新发现的细胞色素c与阴离子磷脂复合物的氧化还原机制及其在健康和疾病中的凋亡途径中的作用。
Since the (re)discovery of cytochrome c (cyt c) in the early 1920s and subsequent detailed characterization of its structure and function in mitochondrial electron transport, it took over 70 years to realize that cyt c plays a different, not less universal role in programmed cell death, apoptosis, by interacting with several proteins and forming apoptosomes. Recently, two additional essential functions of cyt c in apoptosis have been discovered that are carried out via its interactions with anionic phospholipids: a mitochondria specific phospholipid, cardiolipin (CL), and plasma membrane phosphatidylserine (PS). Execution of apoptotic program in cells is accompanied by substantial and early mitochondrial production of reactive oxygen species (ROS). Because antioxidant enhancements protect cells against apoptosis, ROS production was viewed not as a meaningless side effect of mitochondrial disintegration but rather playing some - as yet unidentified - role in apoptosis. This conundrum has been resolved by establishing that mitochondria contain a pool of cyt e, which interacts with CL and acts as a CL oxygenase. The oxygenase is activated during apoptosis, utilizes generated ROS and causes selective oxidation of CL. The oxidized CL is required for the release of pro-apoptotic factors from mitochondria into the cytosol. This redox mechanism of cyt c is realized earlier than its other well-recognized functions in the formation of apoptosomes and caspase activation. In the cytosol, released cyt c interacts with another anionic phospholipid, PS, and catalyzes its oxidation in a similar oxygenase reaction. Peroxidized PS facilitates its externalization essential for the recognition and clearance of apoptotic cells by macrophages. Redox catalysis of plasma membrane PS oxidation constitutes an important redox-dependent function of cyt c in apoptosis and phagocytosis. Thus, cyt c acts as an anionic phospholipid specific oxygenase activated and required for the execution of essential stages of apoptosis. This review is focused on newly discovered redox mechanisms of complexes of cyt c with anionic phospholipids and their role in apoptotic pathways in health and disease.