Mitochondria and GSK-3β in Cardioprotection Against Ischemia/Reperfusion Injury
Mitochondria and GSK-3β in Cardioprotection Against Ischemia/Reperfusion Injury
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DOI：
10.1007/s10557-010-6234-z
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发表时间：
2010-06-01
影响因子：
3.4
通讯作者：
Tanno, Masaya
中科院分区：
文献类型：
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作者：
Miura, Tetsuji;Tanno, Masaya
神经元是细胞的发电站，是细胞信号传导的平台和细胞死亡的决策者，包括缺血/再灌注引起的死亡。局部缺血会关闭线粒体产生ATP的功能，并且细胞活力会因局部缺血期间能量缺乏和细胞毒性代谢产物的积累而受到损害。此外，线粒体通透性转换孔（mPTP）是由缺血引发的开放后再灌注，导致再灌注诱导的细胞坏死。mPTP开放可以通过缺血预处理（IPC）和诱导GSK-3 β磷酸化的其他干预来抑制。线粒体ATP敏感性K+通道（mK（ATP）通道）的激活是IPC触发阶段的重要信号步骤，其最终增强再灌注后GSK-3 β磷酸化，并且该通道也作为细胞保护的介导物发挥作用。线粒体Ca ~（2+）激活的K ~+通道与mK（ATP）通道的作用相似，但其调节机制不同。磷酸化GSK-3 β可能通过多种机制抑制mPTP开放，包括保护mPTP复合物中的己糖激酶II，阻止亲环素-D与腺嘌呤核苷酸移位酶的相互作用，抑制p53激活和减弱缺血期间ATP水解。然而，GSK-3 β磷酸化和其他mPTP调节因子的细胞保护性信号传导途径被合并症（包括2型糖尿病）改变，并且这种改变使得心肌对IPC和其他心脏保护剂不敏感。mPTP的调节机制，以及经常与缺血性心脏病相关的发病率的改变需要进一步表征，以将线粒体和mPTP生物学转化为临床竞技场。
The mitochondrion is a powerhouse of the cell, a platform of cell signaling and decision-maker of cell death, including death by ischemia/reperfusion. Ischemia shuts off ATP production by mitochondria, and cell viability is compromised by energy deficiency and build-up of cytotoxic metabolites during ischemia. Furthermore, the mitochondrial permeability transition pore (mPTP) is primed by ischemia to open upon reperfusion, leading to reperfusion-induced cell necrosis. mPTP opening can be suppressed by ischemic preconditioning (IPC) and other interventions that induce phosphorylation of GSK-3 beta. Activation of the mitochondrial ATP-sensitive K+ channel (mK(ATP) channel) is an important signaling step in a trigger phase of IPC, which ultimately enhances GSK-3 beta phosphorylation upon reperfusion, and this channel functions as a mediator of cytoprotection as well. The mitochondrial Ca2+-activated K+ channel appears to play roles similar to those of the mK(ATP) channel, though regulatory mechanisms of the channels are different. Phosphorylated GSK-3 beta inhibits mPTP opening presumably by multiple mechanisms, including preservation of hexokinase II in mPTP complex, prevention of interaction of cyclophilin-D with adenine nucleotide translocase, inhibition of p53 activation and attenuation of ATP hydrolysis during ischemia. However, cytoprotective signaling pathways to GSK-3 beta phosphorylation and other mPTP regulatory factors are modified by co-morbidities, including type 2 diabetes, and such modification makes the myocardium refractory to IPC and other cardioprotective agents. Regulatory mechanisms of mPTP, and their alterations by morbidities frequently associated with ischemic heart disease need to be further characterized for translation of mitochondrial and mPTP biology to the clinical arena.