title: Sestrin2-AMPK activation protects mitochondrial function against glucose deprivation-induced cytotoxicity.
abstract: Sestrin2 (SESN2) regulates redox-homeostasis and apoptosis in response to various stresses. Although the antioxidant effects of SESN2 have been well established, the roles of SESN2 in mitochondrial function and metabolic stress have not yet been elucidated. In this study, we investigated the role of SESN2 in mitochondrial dysfunction under glucose deprivation and related signaling mechanisms. Glucose deprivation significantly upregulated SESN2 expression in hepatocyte-derived cells. Antioxidant treatments repressed SESN2 induction under glucose deprivation, this result suggested that reactive oxygen species (ROS) production was involved in SESN2 induction. Moreover, NF-E2-related factor-2 (Nrf2) phosphorylation was accompanied in induction of SESN2 by glucose deprivation. To elucidate the functional role of SESN2, we examined cells that stably overexpressed SESN2. Overexpression of SESN2 inhibited glucose deprivation-induced ROS production and cell death. In addition, under glucose deprivation, the changes in mitochondrial membrane potential, ADP/ATP ratio, and mitochondrial DNA content were significantly restored in SESN2-overexpressing cells. Moreover, siRNA knockdown of SESN2 failed to prevent mitochondrial permeability transition by glucose depletion. Mechanistic investigation showed that glucose deprivation significantly increased AMP-activated protein kinase (AMPK) activation. The recovery of mitochondrial function under glucose deprivation in SESN2-overexpressing cells was not seen in SESN2-overexpressing cells transfected with a dominant-negative AMPK; this result suggested that AMPK activation was responsible for SESN2-mediated mitochondrial protection against glucose deprivation. Treatment with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR, an AMPK activator) also provided cytoprotective effects against glucose deprivation. Our findings provide evidence for the functional importance of SESN2-AMPK activation in the protection of mitochondria and cells against glucose deprivation-induced metabolic stress.
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: 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: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000084622:Sestrins
chemical_list: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D005947:Glucose; D006861:Hydrogen Peroxide; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; C465398:SESN2 protein, human; D000084622:Sestrins; C031143:AICA ribonucleotide
keywords: AMPK; Glucose deprivation; Hepatocytes; Mitochondria; Reactive oxygen species; Sestrin2