Halestrap A P, Connern C P, Griffiths E J, Kerr P M
Bristol Heart Institute, University of Bristol, UK.
Mol Cell Biochem. 1997 Sep;174(1-2):167-72.
When loaded with high (pathological) levels of Ca2+, mitochondria become swollen and uncoupled as the result of a large nonspecific increase in membrane permeability. This process, known as the mitochondrial permeability transition (MPT), is exacerbated by oxidative stress and adenine nucleotide depletion. These conditions match those that a heart experiences during reperfusion following a period of ischaemia. The MPT is caused by the opening of a non-specific pore that can be prevented by sub-micromolar concentrations of cyclosporin A (CsA). A variety of conditions that increase the sensitivity of pore opening to [Ca2+], such as thiol modification, oxidative stress, increased matrix volume and chaotropic agents, all enhance the binding of matrix cyclophilin (CyP) to the inner mitochondrial membrane in a CsA-sensitive manner. In contrast, ADP, membrane potential and low pH decrease the sensitivity of pore opening to [Ca2+] without affecting CyP binding. We present a model of pore opening involving CyP binding to a membrane target protein followed by Ca(2+)-dependent triggering of a conformational change to induce channel opening. Using the ischaemic/reperfused rat heart we have shown that the mitochondrial pore does not open during ischaemia, but does do so during reperfusion. Recovery of heart during reperfusion is improved in the presence of 0.2 microM CsA, suggesting that the MPT may be critical in the transition from reversible to irreversible reperfusion injury.
当线粒体负载高（病理）水平的Ca2+时，由于膜通透性的大幅非特异性增加，线粒体就会肿胀并发生解偶联。这个过程，即线粒体通透性转换（MPT），会因氧化应激和腺嘌呤核苷酸耗竭而加剧。这些情况与心脏在缺血一段时间后的再灌注过程中所经历的情况相符。MPT是由一个非特异性孔的开放引起的，亚微摩尔浓度的环孢素A（CsA）可以阻止这种开放。多种增加孔开放对[Ca2+]敏感性的情况，如硫醇修饰、氧化应激、基质体积增加和离液剂，都会以CsA敏感的方式增强基质亲环蛋白（CyP）与线粒体内膜的结合。相反，ADP、膜电位和低pH值会降低孔开放对[Ca2+]的敏感性，而不影响CyP的结合。我们提出了一个孔开放的模型，即CyP与膜靶蛋白结合，随后Ca(2+)依赖性触发构象变化以诱导通道开放。利用缺血/再灌注的大鼠心脏，我们已经表明线粒体孔在缺血期间不会开放，但在再灌注期间会开放。在存在0.2微摩尔CsA的情况下，再灌注期间心脏功能的恢复得到改善，这表明MPT可能在从可逆性再灌注损伤向不可逆性再灌注损伤的转变中起关键作用。
