title: Mitochondrial-generated ROS down regulates insulin signaling via activation of the p38MAPK stress response pathway.
abstract: Impairment of insulin signaling and hepatic insulin resistance has been attributed to ROS-mediated activation of p38MAPK stress response signaling. Our research focused on whether (a) ROS generated by mitochondrial electron transport chain complex I (ETC-CI) dysfunction, via the use of Rotenone, inactivates insulin signaling; and (b) the p38MAPK pathway is involved in the ROS-induced impairment of insulin signaling. Our results show that in primary mouse hepatocytes the CI inhibitor, Rotenone, (a) induces IRS-1 Ser(307) phosphorylation that is blocked by the anti-oxidant NAC or by the p38MAPK inhibitors, SB203580 and SB202190; (b) inhibits insulin-stimulated AKT-Ser(473) and GSK3β-Ser(9) phosphorylations, in a manner that is not responsive to reversal by the anti-oxidant NAC or by the p38MAPK inhibitors, SB203580 and SB202190. We conclude that rotenone-induced insulin resistance involves a p38MAPK-dependent mechanism for the inhibition of the proximal end of insulin signaling (IRS1), and a p38MAPK-independent mechanism for the inhibition of the distal end (AKT and GSK3β). Our study suggests that ROS generated by inhibition of ETC CI, promotes hepatic insulin resistance partly via activation of the p38MAPK stress-response pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, 77555, USA.
authors.forename: Rabab
authors.initials: R
authors.lastname: Al-Lahham
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, 77555, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Deford
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, 77555, USA. Electronic address: jpapacon@utmb.edu.
authors.forename: John
authors.initials: J
authors.lastname: Papaconstantinou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D007093:Imidazoles; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D011725:Pyridines; D017382:Reactive Oxygen Species; D012402:Rotenone; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
keywords: AKT/PKB; GSK3β; IRS-1; Mitochondrial dysfunction; Serine phosphorylation; p38MAPK