Kagan Valerian E, Borisenko Grigory G, Tyurina Yulia Y, Tyurin Vladimir A, Jiang Jianfei, Potapovich Alla I, Kini Vidisha, Amoscato Andrew A, Fujii Yasu
Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Pittsburgh, PA 15260, USA.
Free Radic Biol Med. 2004 Dec 15;37(12):1963-85. doi: 10.1016/j.freeradbiomed.2004.08.016.
The primary life-supporting function of cytochrome c (cyt c) is control of cellular energetic metabolism as a mobile shuttle in the electron transport chain of mitochondria. Recently, cyt c's equally important life-terminating function as a trigger and regulator of apoptosis was identified. This dreadful role is realized through the relocalization of mitochondrial cyt c to the cytoplasm where it interacts with Apaf-1 in forming apoptosomes and mediating caspase-9 activation. Although the presence of heme moiety of cyt c is essential for the latter function, cyt c's redox catalytic features are not required. Lately, two other essential functions of cyt c in apoptosis, that may rely heavily on its redox activity have been suggested. Both functions are directed toward oxidation of two negatively charged phospholipids, cardiolipin (CL) in the mitochondria and phosphatidylserine (PS) in the plasma membrane. In both cases, oxidized phospholipids seem to be essential for the transduction of two distinctive apoptotic signals: one is participation of oxidized CL in the formation of the mitochondrial permeability transition pore that facilitates release of cyt c into the cytosol and the other is the contribution of oxidized PS to the externalization and recognition of PS (and possibly oxidized PS) on the cell surface by specialized receptors of phagocytes. In this review, we present a new concept that cyt c actuates both of these oxidative roles through a uniform mechanism: its specific interactions with each of these phospholipids result in the conversion and activation of cyt c, transforming it from an innocuous electron transporter into a calamitous peroxidase capable of oxidizing the activating phospholipids. We also show that this new concept is compatible with a leading role for reactive oxygen species in the execution of the apoptotic program, with cyt c as the main executioner.
细胞色素c（cyt c）的主要生命维持功能是作为线粒体电子传递链中的移动穿梭体来控制细胞的能量代谢。最近，人们发现cyt c作为细胞凋亡的触发因子和调节因子，同样具有重要的生命终止功能。这种可怕的作用是通过线粒体cyt c重新定位到细胞质中来实现的，在那里它与凋亡蛋白酶激活因子-1（Apaf-1）相互作用，形成凋亡小体并介导半胱天冬酶-9（caspase-9）的激活。虽然cyt c的血红素部分对于后者的功能至关重要，但其氧化还原催化特性并非必需。最近，有人提出cyt c在细胞凋亡中还有另外两个重要功能，这可能严重依赖于其氧化还原活性。这两个功能都指向两种带负电荷的磷脂的氧化，即线粒体中的心磷脂（CL）和质膜中的磷脂酰丝氨酸（PS）。在这两种情况下，氧化的磷脂似乎对于两种不同的凋亡信号的转导至关重要：一种是氧化的CL参与线粒体通透性转换孔的形成，促进cyt c释放到细胞质中；另一种是氧化的PS有助于吞噬细胞的特异性受体将PS（可能还有氧化的PS）外化并识别到细胞表面。在这篇综述中，我们提出了一个新的概念，即cyt c通过一种统一的机制发挥这两种氧化作用：它与每种磷脂的特异性相互作用导致cyt c的转化和激活，将其从一个无害的电子转运体转变为一个能够氧化激活磷脂的灾难性过氧化物酶。我们还表明，这个新概念与活性氧在凋亡程序执行中的主导作用以及cyt c作为主要执行者是相容的。
