AMPK-mediated GSK3β inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress

• Published in: Biochemical pharmacology 2010-05, Vol.79 (9), p.1352-1362
• Main Authors: Choi, Song Hwa, Kim, Young Woo, Kim, Sang Geon
• Format: Article
• Language: English
• Subjects: AMPK; Biological and medical sciences; Cytoprotection; GSK3β; Isoliquiritigenin; Medical sciences; Mitochondrial dysfunction; Pharmacology. Drug treatments
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2009.12.011

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 H 2O 2 production increased by AA + iron, thereby enabling cells to restore GSH content. ILQ treatment enhanced inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β), and prevented a decrease in the GSK3β phosphorylation elicited by AA + iron, which contributed to protecting cells and mitochondria. GSK3β 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 GSK3β phosphorylation. These results demonstrate that ILQ has the ability to protect cells from AA + iron-induced H 2O 2 production and mitochondrial dysfunction, which is mediated with GSK3β phosphorylation downstream of AMPK.