Division of Cardiology, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, 060-8543, Japan.
Cardiovasc Drugs Ther. 2010 Jun;24(3):255-63. doi: 10.1007/s10557-010-6234-z.
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-3beta. 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-3beta phosphorylation upon reperfusion, and this channel functions as a mediator of cytoprotection as well. The mitochondrial Ca(2+)-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-3beta 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-3beta 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.
线粒体是细胞的能量工厂，也是细胞信号转导的平台和细胞死亡的决策者，包括缺血/再灌注引起的细胞死亡。缺血会使线粒体停止产生 ATP，细胞活力因能量缺乏和缺血期间细胞毒性代谢物的积累而受损。此外，线粒体通透性转换孔 (mPTP) 在缺血时被预先激活，在再灌注时开放，导致再灌注引起的细胞坏死。mPTP 的开放可以通过缺血预处理 (IPC) 和其他诱导 GSK-3β磷酸化的干预措施来抑制。线粒体 ATP 敏感性钾通道 (mKATP 通道) 的激活是 IPC 触发阶段的一个重要信号步骤，它最终增强了再灌注时 GSK-3β的磷酸化，并且该通道作为细胞保护的介质起作用。线粒体钙激活钾通道 (mitochondrial Ca2+-activated K+ channel, mBKCa) 的作用似乎与 mKATP 通道相似，尽管通道的调节机制不同。磷酸化的 GSK-3β通过多种机制抑制 mPTP 的开放，包括在 mPTP 复合物中保留己糖激酶 II、防止亲环素-D 与腺嘌呤核苷酸转运体相互作用、抑制 p53 的激活以及减少缺血期间的 ATP 水解。然而，GSK-3β磷酸化和其他 mPTP 调节因子的细胞保护信号通路会因合并症（包括 2 型糖尿病）而发生改变，这种改变使心肌对 IPC 和其他心脏保护剂产生耐药性。需要进一步研究 mPTP 的调节机制及其与缺血性心脏病相关的合并症的改变，以便将线粒体和 mPTP 生物学转化为临床领域。
