AMPK-mediated GSK3β inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress
AMPK-mediated GSK3β inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress
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DOI：
10.1016/j.bcp.2009.12.011
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发表时间：
2010-05-01
影响因子：
5.8
通讯作者：
Kim, Sang Geon
中科院分区：
文献类型：
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作者：
Choi, Song Hwa;Kim, Young Woo;Kim, Sang Geon
异甘草素（ILQ）是一种源自甘草的类黄酮化合物，已知可以激活SIRT1。花生四烯酸（AA）与铁（一种自氧化催化剂）结合会导致细胞产生过多的活性物质，并改变线粒体的通透性转变。鉴于氧化应激在细胞死亡和炎症中的重要性，本研究探讨了ILQ保护细胞免受AA +铁诱导的线粒体损伤的潜力以及这种细胞保护的潜在基础。通过改变与细胞活力相关的蛋白水平，ILQ可以抑制AA +铁诱导的细胞凋亡：ILQ可以阻止Bcl-x(L)的减少，以及聚（adp -核糖）聚合酶和procaspase-3的切割。此外，ILQ抑制了AA +铁引起线粒体功能障碍的能力。此外，ILQ处理可减少线粒体中超氧化物的产生。与此一致的是，ILQ阻止了细胞中AA +铁增加的H2O2产生，从而使细胞恢复GSH含量。ILQ处理增强了糖原合成酶激酶-3 β (GSK3 β)的抑制性磷酸化，并阻止了AA +铁引起的GSK3 β磷酸化的下降，这有助于保护细胞和线粒体。在ILQ磷酸化GSK3 β之前，amp激活的蛋白激酶（AMPK）激活，AMPK也负责线粒体保护，在使用AMPK和化合物c的显性负突变体的实验中，AMPK的作用被逆转。此外，AMPK激活导致GSK3 β磷酸化。这些结果表明ILQ具有保护细胞免受AA +铁诱导的H2O2产生和线粒体功能障碍的能力，这是由AMPK下游的GSK3 β磷酸化介导的。(C) 2009爱思唯尔公司版权所有。
Isoliquiritigenin (ILQ), a flavonoid compound originated from Glycyrrhiza species, is known to activate SIRT1. Arachidonic acid (AA) in combination with iron (a catalyst of auto-oxidation) leads cells to produce excess reactive species with a change in mitochondrial permeability transition. In view of the importance of oxidative stress in cell death and inflammation, this study investigated the potential of ILQ to protect cells against the mitochondrial impairment induced by AA + iron and the underlying basis for this cytoprotection. Treatment with ILQ inhibited apoptosis induced by AA + iron, as evidenced by alterations in the levels of the proteins associated with cell viability: ILQ prevented a decrease in Bcl-x(L), and cleavage of poly(ADP-ribose)polymerase and procaspase-3. Moreover, ILQ inhibited the ability of AA + iron to elicit mitochondrial dysfunction. In addition, superoxide generation in mitochondria was attenuated by ILQ treatment. Consistently, ILQ prevented cellular H2O2 production increased by AA + iron, thereby enabling cells to restore GSH content. ILQ treatment enhanced inhibitory phosphorylation of glycogen synthase kinase-3 beta (GSK3 beta), and prevented a decrease in the GSK3 beta phosphorylation elicited by AA + iron, which contributed to protecting cells and mitochondria. GSK3 beta phosphorylation by ILQ was preceded by AMP-activated protein kinase (AMPK) activation, which was also responsible for mitochondrial protection, as shown by reversal of its effect in the experiments using a dominant negative mutant of AMPK and compound C. Moreover, the AMPK activation led to GSK3 beta phosphorylation. These results demonstrate that ILQ has the ability to protect cells from AA + iron-induced H2O2 production and mitochondrial dysfunction, which is mediated with GSK3 beta phosphorylation downstream of AMPK. (C) 2009 Elsevier Inc. All rights reserved.