A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection
A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection
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DOI：
10.1042/bst0380841
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发表时间：
2010-08-01
影响因子：
3.9
通讯作者：
Halestrap, Andrew P.
中科院分区：
文献类型：
--
作者：
Halestrap, Andrew P.
除了它们在ATP产生和代谢中的正常生理作用之外，线粒体还表现出由线粒体内膜中的非特异性孔的开放介导的暗面。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，会导致坏死细胞死亡。MPTP是开放的Ca 2+超载的反应，特别是当伴随着氧化应激，磷酸盐浓度升高和腺嘌呤核苷酸耗尽。在心肌梗塞或中风的治疗期间和心脏手术期间可能发生的缺血一段时间后，心脏和大脑经历这些病症。本文就MPTP的性质、调控及分子组成等方面进行综述。CyP-D（亲环素D），腺嘌呤核苷酸移位酶和磷酸载体的作用的证据进行了总结和其他潜在的相互作用与线粒体外膜蛋白进行了讨论。然后，我回顾了MPTP开放介导心脏再灌注损伤和MPTP抑制心脏保护的证据。抑制可能涉及MPTP的直接药理学靶向，例如用与CyP-D结合的环孢菌素A，或间接抑制MPTP开放，例如用预处理方案。这些调用复杂的信号传导途径，以减少氧化应激和Ca 2+负荷。MPTP抑制剂还在高血压动物模型中保护免于充血性心力衰竭。因此，MPTP是临床实践中非常有前途的药理学靶点，特别是一旦开发出更特异的药物。
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 Ca2+ 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 Ca2+ 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.