Lemasters John J, Qian Ting, He Lihua, Kim Jae-Sung, Elmore Steven P, Cascio Wayne E, Brenner David A
Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina 27599-7090, USA.
Antioxid Redox Signal. 2002 Oct;4(5):769-81. doi: 10.1089/152308602760598918.
Inhibition of mitochondrial oxidative phosphorylation progresses to uncoupling when opening of cyclosporin A-sensitive permeability transition pores increases permeability of the mitochondrial inner membrane to small solutes. Involvement of the mitochondrial permeability transition (MPT) in necrotic and apoptotic cell death is implicated by demonstrations of protection by cyclosporin A against oxidative stress, ischemia/reperfusion, tumor necrosis factor-alpha exposure, Fas ligation, calcium overload, and a variety of toxic chemicals. Confocal microscopy directly visualizes the MPT in single mitochondria within living cells from the translocation of impermeant fluorophores, such as calcein, across the inner membrane. Simultaneously, mitochondria release potential-indicating fluorophores. Subsequently, mitochondria swell, causing outer membrane rupture and release of cytochrome c and other proapoptotic proteins from the intermembrane space. In situ a sequence of decreased NAD(P)H, increased free calcium, and increased reactive oxygen species formation within mitochondria promotes the MPT and subsequent cell death. Necrotic and apoptotic cell death after the MPT depends, in part, on ATP levels. If ATP levels fall profoundly, glycine-sensitive plasma membrane permeabilization and rupture ensue. If ATP levels are partially maintained, apoptosis follows the MPT. The MPT also signals mitochondrial autophagy, a process that may be important in removing damaged mitochondria. Cellular features of necrosis, apoptosis, and autophagy frequently occur together after death signals and toxic stresses. A new term, necrapoptosis, describes such death processes that begin with a common stress or death signal, progress by shared pathways, but culminate in either cell lysis (necrosis) or programmed cellular resorption (apoptosis), depending on modifying factors such as ATP.
当环孢素A敏感的通透性转换孔开放增加线粒体内膜对小溶质的通透性时，线粒体氧化磷酸化的抑制会发展为解偶联。环孢素A对氧化应激、缺血/再灌注、肿瘤坏死因子-α暴露、Fas连接、钙超载及多种有毒化学物质具有保护作用，这表明线粒体通透性转换（MPT）参与坏死和凋亡性细胞死亡。共聚焦显微镜通过诸如钙黄绿素等非渗透性荧光团跨内膜的移位，直接观察活细胞中单一线粒体内的MPT。同时，线粒体释放电位指示荧光团。随后，线粒体肿胀，导致外膜破裂，细胞色素c和其他促凋亡蛋白从膜间隙释放。在线粒体内，NAD(P)H减少、游离钙增加和活性氧生成增加的一系列变化促进MPT及随后的细胞死亡。MPT后的坏死和凋亡性细胞死亡部分取决于ATP水平。如果ATP水平大幅下降，就会发生甘氨酸敏感的质膜通透性增加和破裂。如果ATP水平部分维持，则MPT后会发生凋亡。MPT还标志着线粒体自噬，这一过程在清除受损线粒体方面可能很重要。在死亡信号和毒性应激后，坏死、凋亡和自噬的细胞特征经常同时出现。一个新术语“坏死凋亡”描述了这样的死亡过程，即始于共同的应激或死亡信号，通过共同途径发展，但根据ATP等调节因素，最终导致细胞裂解（坏死）或程序性细胞吸收（凋亡）。
