Dubin M, Stoppani A O
Centro de Investigaciones Bioenergéticas, Facultad de Medicina (UBA-CONICET), Universidad de Buenos Aires.
Medicina (B Aires). 2000;60(3):375-86.
Physiological cell death and apoptosis are natural processes genetically programmed, subjected to control by complex molecular mechanisms which elucidation is of particular interest for biology and medicine. Mitochondria play an essential role in physiological cell death and apoptosis. Apoptogenic effects develop in three phases, namely: (a) premitochondrial; (b) mitochondrial and (c) post-mitochondrial. During the first phase, apoptogenic signals (genotoxic agents, oxygen free radicals, corticoids, antibodies, etc.) interact with cell receptors activating specific mechanisms including thiol dependent proteases (caspases). As a consequence of those signals, mitochondrial damage results (membrane permeabilization, collapse of the membrane potential, swelling, membrane disruption, inhibition of electron transfer and oxidative phosphorylation). Other consequences of the mitochondrial disruption are the enhancement of free radical production and the exit of cytochrome c, caspases and endonucleases to the cytosol. During the third phase of apoptosis, free radicals and activated enzymes attack the cell protein structure and ADN, thus causing cell death. The mitochondrial regulation of apoptosis is controlled by the mitochondrial transitory permeability pore (MTPP) which is constituted by caspases, hexokinases, cytochrome c, ATP and ADP. MTPP is subjected to control by apoptogenic or antiapoptogenic agents which open or close it, according to their structure and the cell metabolic conditions. Uncontrolled opening of MTPP determines a massive exit of mitochondrial apoptogenic factors which in the cytosol and the nucleus exert their apoptogenic effects, thus producing cell death. MTPP can be modified by drugs with potential therapeutic actions thus opening interesting therapeutic possibilities. The role of apoptosis in pathologies such as degenerative diseases of the nervous system, autoimmunity diseases, SIDA and cancer is discussed.
生理性细胞死亡和凋亡是由基因编程的自然过程，受复杂分子机制的控制，其阐释对生物学和医学尤为重要。线粒体在生理性细胞死亡和凋亡中起关键作用。凋亡效应分三个阶段发展，即：(a) 线粒体前阶段；(b) 线粒体阶段；(c) 线粒体后阶段。在第一阶段，凋亡信号（遗传毒性剂、氧自由基、皮质类固醇、抗体等）与细胞受体相互作用，激活包括硫醇依赖性蛋白酶（半胱天冬酶）在内的特定机制。这些信号的结果是导致线粒体损伤（膜通透性增加、膜电位崩溃、肿胀、膜破裂、电子传递和氧化磷酸化抑制）。线粒体破坏的其他后果是自由基产生增加以及细胞色素c、半胱天冬酶和核酸内切酶释放到细胞质中。在凋亡的第三阶段，自由基和活化的酶攻击细胞蛋白质结构和DNA，从而导致细胞死亡。凋亡的线粒体调节由线粒体瞬时通透性孔（MTPP）控制，MTPP由半胱天冬酶、己糖激酶、细胞色素c、ATP和ADP组成。MTPP受凋亡或抗凋亡剂的控制，这些试剂根据其结构和细胞代谢条件使其开放或关闭。MTPP的不受控制的开放决定了线粒体凋亡因子的大量释放，这些因子在细胞质和细胞核中发挥其凋亡作用，从而导致细胞死亡。MTPP可被具有潜在治疗作用的药物修饰，从而开启了有趣的治疗可能性。本文讨论了凋亡在诸如神经系统退行性疾病、自身免疫性疾病、艾滋病和癌症等病理过程中的作用。
