Resveratrol Protects Mitochondria against Oxidative Stress through AMP-Activated Protein Kinase-Mediated Glycogen Synthase Kinase-3β Inhibition Downstream of Poly(ADP-ribose)polymerase-LKB1 Pathway

Abstract

Arachidonic acid (AA, a proinflammatory fatty acid) in combination with iron promotes excess reactive oxygen species (ROS) production and exerts a deleterious effect on mitochondria. We have shown previously that activation of AMP-activated protein kinase (AMPK) protects hepatocytes from AA ϩ iron-induced apoptosis. Resveratrol, a polyphenol in grapes, has beneficial effects mediated through SIRT1, LKB1, and AMPK. This study investigated the potential of resveratrol to protect against the mitochondrial impairment induced by AA ϩ iron and the underlying mechanism for this cytoprotection. Resveratrol treatment inhibited apoptosis, ROS production, and glutathione depletion elicited by AA ϩ iron in HepG2 cells. In addition, resveratrol attenuated superoxide generation in mitochondria and inhibited mitochondrial dysfunction induced by AA ϩ iron. Overall, AMPK activation by resveratrol contributed to cell survival, as supported by the reversal of its restoration of mitochondrial membrane potential by either overexpression of a dominant-negative mutant of AMPK␣ or compound C treatment. Resveratrol increased inhibitory phosphorylation of glycogen synthase kinase-3␤ (GSK3␤) downstream of AMPK, which contributed to mitochondrial protection and cell survival. Likewise, small interfering RNA knockdown of LKB1, an upstream kinase of AMPK, reduced the ability of resveratrol to protect cells from mitochondrial dysfunction. Furthermore, this LKB1-dependent mitochondrial protection resulted from resveratrol's poly(ADP-ribose)polymerase activation, but not SIRT1 activation, as supported by the experiment using 3-aminobenzamide, a poly(ADP-ribose)polymerase inhibitor. Other polyphenols, such as apigenin, genistein, and daidzein, did not activate AMPK or protect mitochondria against AA ϩ iron. Thus, resveratrol protects cells from AA ϩ iron-induced ROS production and mitochondrial dysfunction through AMPKmediated inhibitory phosphorylation of GSK3␤ downstream of poly(ADP-ribose)polymerase-LKB1 pathway.

Proenergetic effects of resveratrol in the murine neuronal cell line Neuro2a

“…One reason could be that resveratrol might improve mitochondrial function; thereby more lactate could enter the next steps (citric acid cycle and oxidative phosphorylation) and produce a boost of ATP. This hypothesis is in agreement with other studies that also reported resveratrol to be able to protect cells from mitochondrial dysfunction and to increase the number of mitochondria [45][46][47].…”

“…The powerhouse of energy production, mitochondrial function and number primarily impact on the supply of ATP [55]. Numerous studies in the literature also reported resveratrol protected cells from mitochondrial dysfunction [45][46][47]. Interestingly, resveratrol was found to increase the number of mitochondria in various cell lines and tissues, such as in Neuro2a cells [28], endothelial cells [56] and muscle [45].…”

20(S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway

“…recently, aMPK was shown to be involved in cellular homeostasis and emerged as a pivot point between cell survival and apoptosis (16)(17)(18). Previous studies have reported that aMPK activation regulates apoptosis in cancer cells via a signaling pathway that includes the up-regulation of p53 protein, activation of caspases, generation of roS and inhibition of the proteolytic cleavage of poly (adP-ribose) polymerase (ParP)-lKB1 (17)(18)(19)(20).…”

Resveratrol Triggers Apoptosis Through Regulating Ceramide Metabolizing Genes in Human K562 Chronic Myeloid Leukemia Cells

“…Resveratrol has been reported to have cytotoxic effects on various types of cancers (1). On the other hand, resveratrol has been shown to be apoptotic, autophagocytic, a radiotherapy-sensitizer, a cell cycle arrester, an inhibitor of ROS generation in mitochondria, and a regulator of p53 in many cancers (4,5,7,(18)(19)(20). One of the most important properties of resveratrol is that it has selective toxic effects on cancer cells and far less effect on normal, healthy cells (21).…”