Jemmerson Ronald, Dubinsky Janet M, Brustovetsky Nickolay
Department of Microbiology and Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1158-72. doi: 10.1089/ars.2005.7.1158.
Apoptosis is critical for normal development and tissue homeostasis. However, its abnormal occurrence has been implicated in a number of disorders, including neurodegenerative diseases and stroke. Translocation of cytochrome c (Cyt c) from mitochondria to the cytoplasm is a key step in the initiation and/or amplification of apoptosis. Here we discuss Cyt c release in apoptosis with its impact on the CNS and review our studies of Cyt c release from isolated rat brain mitochondria in response to several insults. Calcium-induced Cyt c release, as occurs in neurons during stroke and ischemia, involves rupture of the mitochondrial outer membrane (MOM) and can be blocked by inhibitors of the mitochondrial permeability transition (mPT). Thus, inhibitors of the mPT have shown efficacy in animal models of ischemia. In contrast, proapoptotic proteins, such as BID, BAX, and BAK, induce Cyt c release independently of the mPT without lysing the MOM. Several inhibitors of BAX-induced Cyt c release have shown promise in models of CNS apoptosis. Because of their distinct mechanisms for Cyt c release, both the mPT and proapoptotic proteins should be targeted for effective clinical intervention in CNS disorders involving apoptosis.
细胞凋亡对于正常发育和组织稳态至关重要。然而，其异常发生与多种疾病有关，包括神经退行性疾病和中风。细胞色素c（Cyt c）从线粒体向细胞质的转位是细胞凋亡启动和/或放大的关键步骤。在此，我们讨论细胞凋亡过程中Cyt c的释放及其对中枢神经系统的影响，并回顾我们关于分离的大鼠脑线粒体在几种损伤刺激下Cyt c释放的研究。钙诱导的Cyt c释放，如在中风和缺血期间神经元中发生的那样，涉及线粒体外膜（MOM）的破裂，并且可被线粒体通透性转换（mPT）抑制剂阻断。因此，mPT抑制剂已在缺血动物模型中显示出疗效。相比之下，促凋亡蛋白，如BID、BAX和BAK，独立于mPT诱导Cyt c释放而不裂解MOM。几种BAX诱导的Cyt c释放抑制剂已在中枢神经系统细胞凋亡模型中显示出前景。由于它们释放Cyt c的机制不同，mPT和促凋亡蛋白都应作为涉及细胞凋亡的中枢神经系统疾病有效临床干预的靶点。
