Bayir H, Fadeel B, Palladino M J, Witasp E, Kurnikov I V, Tyurina Y Y, Tyurin V A, Amoscato A A, Jiang J, Kochanek P M, DeKosky S T, Greenberger J S, Shvedova A A, Kagan V E
Center for Free Radical and Antioxidant Health, Pittsburgh, PA 15219, USA.
Biochim Biophys Acta. 2006 May-Jun;1757(5-6):648-59. doi: 10.1016/j.bbabio.2006.03.002. Epub 2006 Mar 31.
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 c, 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.
自20世纪20年代初细胞色素c（cyt c）被（重新）发现，以及随后对其在线粒体电子传递中的结构和功能进行详细表征以来，人们花了70多年才认识到cyt c在程序性细胞死亡（即凋亡）中发挥着不同但同样普遍的作用，它通过与多种蛋白质相互作用并形成凋亡小体来实现这一作用。最近，人们又发现了cyt c在凋亡中的另外两个重要功能，这是通过它与阴离子磷脂的相互作用来实现的：一种线粒体特异性磷脂，心磷脂（CL），以及质膜磷脂酰丝氨酸（PS）。细胞中凋亡程序的执行伴随着线粒体大量且早期产生活性氧（ROS）。由于抗氧化剂增强可保护细胞免受凋亡，因此ROS的产生并非被视为线粒体解体的无意义副作用，而是在凋亡中发挥某种尚未明确的作用。通过确定线粒体中存在一组与CL相互作用并作为CL加氧酶的cyt c，这个难题得以解决。该加氧酶在凋亡过程中被激活，利用产生的ROS并导致CL的选择性氧化。氧化的CL是促凋亡因子从线粒体释放到细胞质所必需的。cyt c的这种氧化还原机制比其在凋亡小体形成和半胱天冬酶激活中其他广为人知的功能更早实现。在细胞质中，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。过氧化的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。质膜PS氧化的氧化还原催化构成了cyt c在凋亡和吞噬作用中重要的氧化还原依赖性功能。因此，cyt c作为一种阴离子磷脂特异性加氧酶，在凋亡的关键阶段被激活且是执行这些阶段所必需的。本综述聚焦于新发现的cyt 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状态下凋亡途径中的作用。
