Mitochondrial-generated ROS down regulates insulin signaling via activation of the p38MAPK stress response pathway

Rabab Al Lahham, James H. Deford, John Papaconstantinou

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 Ser307 phosphorylation that is blocked by the anti-oxidant NAC or by the p38MAPK inhibitors, SB203580 and SB202190; (b) inhibits insulin-stimulated AKT-Ser473 and GSK3β-Ser9 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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalMolecular and Cellular Endocrinology
Volume419
DOIs
StatePublished - Jan 5 2016

Fingerprint

Down-Regulation
Rotenone
Chemical activation
Insulin
Insulin Resistance
Oxidants
Phosphorylation
Electron Transport Complex I
Liver
Hepatocytes
Research
SB 203580
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole

Keywords

  • AKT/PKB
  • GSK3β
  • IRS-1
  • Mitochondrial dysfunction
  • P38MAPK
  • Serine phosphorylation

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology
  • Biochemistry

Cite this

Mitochondrial-generated ROS down regulates insulin signaling via activation of the p38MAPK stress response pathway. / Al Lahham, Rabab; Deford, James H.; Papaconstantinou, John.

In: Molecular and Cellular Endocrinology, Vol. 419, 05.01.2016, p. 1-11.

Research output: Contribution to journalArticle

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