title: Resveratrol attenuates methylglyoxal-induced mitochondrial dysfunction and apoptosis by Sestrin2 induction.
abstract: Methylglyoxal is found in high levels in the blood and other tissues of diabetic patients and exerts deleterious effects on cells and tissues. Previously, we reported that resveratrol, a polyphenol in grapes, induced the expression of Sestrin2 (SESN2), a novel antioxidant protein, and inhibited hepatic lipogenesis. This study investigated whether resveratrol protects cells from the methylglyoxal-induced toxicity via SESN2 induction. Methylglyoxal significantly induced cell death in HepG2 cells. However, cells pretreated with resveratrol were rescued from methylglyoxal-induced apoptosis. Resveratrol attenuated glutathione (GSH) depletion and ROS production promoted by methylglyoxal. Moreover, mitochondrial damage was observed by methylglyoxal treatment, but resveratrol restored mitochondrial function, as evidenced by the observed lack of mitochondrial permeability transition and increased ADP/ATP ratio. Resveratrol treatment inhibited SESN2 depletion elicited by methylglyoxal. SESN2 overexpression repressed methylglyoxal-induced mitochondrial dysfunction and apoptosis. Likewise, rotenone-induced cytotoxicity was not observed in SESN2 overexpressed cells. Furthermore, siRNA knockdown of SESN2 reduced the ability of resveratrol to prevent methylglyoxal-induced mitochondrial permeability transition. In addition, when mice were exposed to methylglyoxal after infection of Ad-SESN2, the plasma levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and GSH depletion by methylglyoxal in liver was reduced in Ad-SESN2 infected mice. Our results demonstrated that resveratrol is capable of protecting cells from methylglyoxal-induced mitochondrial dysfunction and oxidative stress via SESN2 induction.
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 501-759, South Korea.
authors.forename: Kyuhwa
authors.initials: K
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 501-759, South Korea.
authors.forename: Suho
authors.initials: S
authors.lastname: Seo
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 501-759, South Korea.
authors.forename: Jae Yun
authors.initials: JY
authors.lastname: Han
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 501-759, South Korea.
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ki
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 501-759, South Korea. Electronic address: smshin@chosun.ac.kr.
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Shin
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011765:Pyruvaldehyde / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D000084622:Sestrins
chemical_list: D017127:Glycation End Products, Advanced; D009687:Nuclear Proteins; D011765:Pyruvaldehyde; D017382:Reactive Oxygen Species; D000077185:Resveratrol; D013267:Stilbenes; C465398:SESN2 protein, human; D000084622:Sestrins
keywords: Methylglyoxal; Mitochondrial dysfunction; Oxidative stress; Reactive oxygen species; Resveratrol; Sestrin2