Department of Biochemistry and The Bristol Heart Institute, University of Bristol, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.
Biochem Soc Trans. 2010 Aug;38(4):841-60. doi: 10.1042/BST0380841.
In addition to their normal physiological role in ATP production and metabolism, mitochondria exhibit a dark side mediated by the opening of a non-specific pore in the inner mitochondrial membrane. This mitochondrial permeability transition pore (MPTP) causes the mitochondria to breakdown rather than synthesize ATP and, if unrestrained, leads to necrotic cell death. The MPTP is opened in response to Ca(2+) overload, especially when accompanied by oxidative stress, elevated phosphate concentration and adenine nucleotide depletion. These conditions are experienced by the heart and brain subjected to reperfusion after a period of ischaemia as may occur during treatment of a myocardial infarction or stroke and during heart surgery. In the present article, I review the properties, regulation and molecular composition of the MPTP. The evidence for the roles of CyP-D (cyclophilin D), the adenine nucleotide translocase and the phosphate carrier are summarized and other potential interactions with outer mitochondrial membrane proteins are discussed. I then review the evidence that MPTP opening mediates cardiac reperfusion injury and that MPTP inhibition is cardioprotective. Inhibition may involve direct pharmacological targeting of the MPTP, such as with cyclosporin A that binds to CyP-D, or indirect inhibition of MPTP opening such as with preconditioning protocols. These invoke complex signalling pathways to reduce oxidative stress and Ca(2+) load. MPTP inhibition also protects against congestive heart failure in hypertensive animal models. Thus the MPTP is a very promising pharmacological target for clinical practice, especially once more specific drugs are developed.
除了在线粒体中产生和代谢 ATP 的正常生理作用外，线粒体还表现出一种由线粒体内膜中非特异性孔开放介导的暗面。这种线粒体通透性转换孔 (MPTP) 导致线粒体分解而不是合成 ATP，如果不受限制，会导致细胞坏死性死亡。MPTP 是在 Ca(2+) 过载的情况下打开的，特别是在伴有氧化应激、磷酸盐浓度升高和腺嘌呤核苷酸耗竭的情况下。这些情况发生在心脏和大脑经历缺血后再灌注时，例如在心肌梗死或中风治疗期间以及心脏手术期间。在本文中，我回顾了 MPTP 的特性、调节和分子组成。总结了 CyP-D（亲环素 D）、腺嘌呤核苷酸转运体和磷酸盐载体的作用证据，并讨论了与外线粒体膜蛋白的其他潜在相互作用。然后，我回顾了 MPTP 开放介导心脏再灌注损伤的证据以及 MPTP 抑制的心脏保护作用。抑制可能涉及 MPTP 的直接药理学靶向，例如与 CyP-D 结合的环孢素 A，或间接抑制 MPTP 开放，例如预处理方案。这些方案通过减少氧化应激和 Ca(2+) 负荷来调用复杂的信号通路。MPTP 抑制还可以防止高血压动物模型中的充血性心力衰竭。因此，MPTP 是临床实践中非常有前途的药理学靶点，尤其是一旦开发出更具特异性的药物。
