XIth Villa Vigoni Conference ‘Redox regulation and the metabolic syndrome’. Villa Vigoni, Loveno di Menaggio, Italy, 23–26 March 2011

First, how the concept of redox reactions as part of a ‘stress response’ evolved into that of genuine ‘physiological controllers’ of cell functions was presented. An equilibrium between signaling and toxicity of reactive oxygen species (ROS) can be basically explained by chemical reactions following a ‘two electron’ or a ‘one electron’ oxidation pathway, respectively. Thiol redox homeostasis was then discussed, exploiting genetic tools to demonstrate that in yeast glutathione (GSH) is essential for life, though concentrations above normal provoke reductive stress, elicit an unfolded protein response and cell death. Although GSH regulates iron metabolism, it is thioredoxin that maintains the cytoplasmic thiol redox balance. The effect of tyrosine nitration in insulin resistance was then presented to show that the protein kinase B/Akt-signaling impacts on glucose transporter 4 (GLUT4) translocation in myotubes. Angiotensin II blocked GLUT4 translocation by producing peroxynitrite (ONOO−), thus nitrating and inhibiting Akt, both in vitro and in vivo. Redox regulation, and particularly the role of nitric oxide (NO), was discussed for endothelial cells with reference to post-translational protein modifications by tyrosine nitration, S-nitrosylation and S-glutathionylation. Redox perturbations initiated by cyclosporine A caused manganese superoxide dismutase nitration, thus causing its inhibition and subsequent mitochondria-dependent death. Plasma membrane redox systems were then reviewed to describe the role of NADPH oxidases (Nox1-5 and Duox1-2), NAD(P)H:quinine oxidoreductase 1 (NQO1), disulfide–thiol exchangers, voltage-dependent anion selective channels 1–3, duodenal cytochrome b, and cytochrome b5 reductase. Alterations of these carriers in obesity, cardiovascular diseases and insulin resistance were discussed. The redox signaling session ended with a talk on MAPK-dependent signaling. By using knockout mice for p38 MAPK, it was shown that the δ form is specifically involved in inhibiting insulin secretion by blocking exocytosis in β cells. This effect occurred through an inhibitory phosphorylation of protein kinase D1, thereby modulating trans-Golgi network.

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