Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore.
Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore.
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发表时间：
2004
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通讯作者：
M. Juhaszova;D. Zorov;Suhn Hee Kim;S. Pepe;Qin Fu;K. Fishbein;B. Ziman;Su-yang Wang;K. Ytrehus-K.-Ytr
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作者：
M. Juhaszova;D. Zorov;Suhn Hee Kim;S. Pepe;Qin Fu;K. Fishbein;B. Ziman;Su-yang Wang;K. Ytrehus-K.-Ytr
环境压力集中在可以触发或抑制细胞死亡的线粒体上。可兴奋的有丝分裂后细胞，在对亚致死的有害应激的反应中，参与了对随后的损伤提供保护的机制。我们发现，长时间缺氧后的再氧化降低了心肌细胞线粒体通透性转变（MPT）的活性氧（ROS）阈值，细胞存活与去极化线粒体的比例呈显著负相关。细胞保护表现出记忆（预适应）是由于触发线粒体肿胀，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)。另外，受体酪氨酸激酶或某些G蛋白偶联受体激活通过蛋白激酶B/Akt和mTOR/p70（s6k）途径、PKC途径或蛋白激酶A途径抑制gsk -3 β，从而引起细胞保护（没有线粒体肿胀或持久记忆）。通过抑制gsk -3 β对末端执行器（通透性过渡孔复合物）的抑制，这些途径的收敛，以限制MPT的诱导，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.