Lemasters J J, Nieminen A L, Qian T, Trost L C, Herman B
Department of Cell Biology and Anatomy, School of Medicine University of North Carolina, Chapel Hill 27799-7090, USA.
Mol Cell Biochem. 1997 Sep;174(1-2):159-65.
Opening of a non-specific, high conductance permeability transition pore or megachannel in the inner mitochondrial membrane causes onset of the mitochondrial permeability transition, which is characterized by mitochondrial swelling, depolarization and uncoupling. Inducers of the permeability transition include Ca2+, oxidant stress and a permissive pH greater than 7.0. Blockers include cyclosporin A, trifluoperazine and pH < 7. Using laser scanning confocal microscopy, we developed techniques to visualize onset of the mitochondrial permeability transition in situ in living cells. In untreated cells, the permeability transition pore is continuously closed and does not 'flicker' open. By contrast, the pore opens in liver and heart cells after exposure to oxidant chemicals, calcium ionophore, hypoxia and ischemia/reperfusion, causing mitochondrial uncoupling and aggravation of ATP depletion. In injury to hepatocytes from tert-butylhydroperoxide, an analog of lipid hydroperoxides generated during oxidative stress, onset of the mitochondrial permeability transition is preceded by oxidation of mitochondrial pyridine nucleotides, mitochondrial generation of oxygen radicals and an increase of mitochondrial Ca2+, all inducers of the mitochondrial permeability transition. In ischemia, the acidosis of anaerobic metabolism protects strongly against cell death. During reperfusion, recovery of pH to normal levels is a stress that actually precipitates cell killing. Onset of the mitochondrial permeability transition may be responsible, in part, for this pH-dependent injury, or pH paradox. The mitochondrial permeability transition may also be responsible for a variety of pathological phenomena. In particular, the mitochondrial permeability transition may underlie Reye's syndrome and Reye's-like drug toxicities. In conclusion, multiple mechanisms contribute to cell injury after hypoxia, ischemia/reperfusion and toxic chemicals, but a common final pathway leading to acute cellular necrosis may be ATP depletion after mitochondrial failure. One important mechanism causing mitochondrial failure is the mitochondrial permeability transition, which both uncouples oxidative phosphorylation and accelerates ATP hydrolysis. Interventions that block this pH-dependent phenomenon protect against onset of cell death.
线粒体内膜中一个非特异性、高电导的通透性转换孔道或大通道的开放会引发线粒体通透性转换，其特征为线粒体肿胀、去极化和解偶联。通透性转换的诱导因素包括Ca2+、氧化应激以及pH大于7.0的适宜环境。阻滞剂包括环孢素A、三氟拉嗪以及pH小于7。利用激光扫描共聚焦显微镜，我们开发了一些技术来在活细胞中原位观察线粒体通透性转换的起始过程。在未处理的细胞中，通透性转换孔道持续关闭，不会“闪烁”打开。相比之下，在暴露于氧化化学物质、钙离子载体、缺氧和缺血/再灌注后，肝脏和心脏细胞中的孔道会打开，导致线粒体解偶联以及ATP耗竭加剧。在叔丁基过氧化氢（氧化应激期间产生的脂质氢过氧化物类似物）对肝细胞造成损伤时，线粒体通透性转换的起始之前会出现线粒体吡啶核苷酸的氧化、线粒体氧自由基的产生以及线粒体Ca2+的增加，这些都是线粒体通透性转换的诱导因素。在缺血过程中，无氧代谢的酸中毒可强烈保护细胞免于死亡。在再灌注期间，pH恢复到正常水平是一种实际上会引发细胞死亡的应激。线粒体通透性转换的起始可能部分导致了这种pH依赖性损伤，即pH反常现象。线粒体通透性转换也可能是多种病理现象的原因。特别是，线粒体通透性转换可能是瑞氏综合征和类瑞氏药物毒性的基础。总之，多种机制导致缺氧、缺血/再灌注和有毒化学物质后的细胞损伤，但导致急性细胞坏死的一个共同最终途径可能是线粒体功能衰竭后的ATP耗竭。导致线粒体功能衰竭的一个重要机制是线粒体通透性转换，它既使氧化磷酸化解偶联，又加速ATP水解。阻断这种pH依赖性现象的干预措施可防止细胞死亡的起始。
