Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury
Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury
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DOI：
10.1023/a:1006879618176
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发表时间：
1997-09-01
影响因子：
4.3
通讯作者：
Kerr, PM
中科院分区：
文献类型：
--
作者：
Halestrap, AP;Connern, CP;Kerr, PM
当负载高（病理）水平的Ca2+时，线粒体变得肿胀和解耦，这是膜通透性大量非特异性增加的结果。这一过程被称为线粒体通透性转变（MPT），氧化应激和腺嘌呤核苷酸耗竭加剧了这一过程。这些情况与心脏缺血一段时间后再灌注时的情况相吻合。MPT是由非特异性孔的打开引起的，可以通过亚微摩尔浓度的环孢素a （CsA）来预防。各种增加气孔打开对[Ca2+]的敏感性的条件，如硫醇修饰、氧化应激、增加基质体积和混沌剂，都以csa敏感的方式增强了基质亲环蛋白（CyP）与线粒体内膜的结合。相比之下，ADP、膜电位和低pH降低了气孔对[Ca2+]的敏感性，但不影响CyP的结合。我们提出了一个涉及CyP与膜靶蛋白结合的孔隙打开模型，随后是Ca2+依赖性触发构象变化以诱导通道打开。使用缺血/再灌注大鼠心脏，我们已经证明线粒体孔在缺血期间不开放，但在再灌注期间开放。0.2 μ M CsA可改善再灌注时心脏的恢复，提示MPT可能是可逆再灌注损伤向不可逆再灌注损伤转变的关键。
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 Ca2+-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 mu M CsA, suggesting that the MPT may be critical in the transition from reversible to irreversible reperfusion injury.