Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore
Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore
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DOI：
10.1172/jci200419906
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发表时间：
2004-06-01
影响因子：
15.9
通讯作者：
Sollott, SJ
中科院分区：
文献类型：
--
作者：
Juhaszova, M;Zorov, DB;Sollott, SJ
环境压力集中在线粒体上，可以触发或抑制细胞死亡。兴奋，有丝分裂后的细胞，在响应亚致死伤害性应激，从事机制，提供保护，从随后的侮辱。我们发现，长时间缺氧后的复氧降低了心肌细胞线粒体通透性转换（MPT）的活性氧（ROS）阈值，细胞存活率与去极化线粒体的分数呈显著负相关。表现出记忆（预处理）的细胞保护是由触发的线粒体肿胀引起的，线粒体肿胀导致底物氧化和ROS产生增强，导致PKC的氧化还原激活，从而抑制糖原合成酶激酶-3 β（GSK-3 β）。或者，受体酪氨酸激酶或某些G蛋白偶联受体活化通过抑制GSK-3 β，经由蛋白激酶B/Akt和mTOR/p70（s6 k）途径、PKC途径或蛋白激酶A途径，增强细胞保护（没有线粒体肿胀或持久记忆）。这些途径通过抑制GSK-3 β对末端效应物（渗透性转换孔复合物）的作用以限制MPT诱导而会聚，这是心肌细胞保护的一般机制。
Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, postmitotic cells, in response to sublethal noxious stress, engage mechanisms that afford protection from subsequent insults. We show that reoxygenation after prolonged hypoxia reduces the reactive oxygen species (ROS) threshold for the mitochondrial permeability transition (MPT) in cardiomyocytes and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria. Cell protection that exhibits a memory (preconditioning) results from triggered mitochondrial swelling that causes enhanced substrate oxidation and ROS production, leading to redox activation of PKC, which inhibits glycogen synthase kinase-3beta (GSK-3beta). Alternatively, receptor tyrosine kinase or certain G protein-coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3beta, via protein kinase B/Akt and mTOR/p70(s6k) pathways, PKC pathways, or protein kinase A pathways. The convergence of these pathways via inhibition of GSK-3beta on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection.