title: Mitochondrial protection by the thioredoxin-2 and glutathione systems in an in vitro endothelial model of sepsis.
abstract: Oxidative stress and mitochondrial dysfunction are common features in patients with sepsis and organ failure. Within mitochondria, superoxide is converted into hydrogen peroxide by MnSOD (manganese-containing superoxide dismutase), which is then detoxified by either the mGSH (mitochondrial glutathione) system, using the enzymes mGPx-1 (mitochondrial glutathione peroxidase-1), GRD (glutathione reductase) and mGSH, or the TRX-2 (thioredoxin-2) system, which uses the enzymes PRX-3 (peroxiredoxin-3) and TRX-2R (thioredoxin reductase-2) and TRX-2. In the present paper we investigated the relative contribution of these two systems, using selective inhibitors, in relation to mitochondrial dysfunction in endothelial cells cultured with LPS (lipopolysaccharide) and PepG (peptidoglycan). Specific inhibition of both the TRX-2 and mGSH systems increased the intracellular total radical production (P<0.05) and reduced mitochondrial membrane potentials (P<0.05). Inhibition of the TRX-2 system, but not mGSH, resulted in lower ATP production (P<0.001) with high metabolic activity (P<0.001), low oxygen consumption (P<0.001) and increased lactate production (P<0.001) and caspase 3/7 activation (P<0.05). Collectively these results show that the TRX-2 system appears to have a more important role in preventing mitochondrial dysfunction than the mGSH system in endothelial cells under conditions that mimic a septic insult.
authors.affiliation: Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Damon A
authors.initials: DA
authors.lastname: Lowes
authors.forename: Helen F
authors.initials: HF
authors.lastname: Galley
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism*; D005978:Glutathione / Q000235:genetics / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D061105:Peroxiredoxin III / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism*; D054482:Thioredoxin Reductase 2 / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D000094765:Glutathione Peroxidase GPX1
chemical_list: D013879:Thioredoxins; D061105:Peroxiredoxin III; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D054482:Thioredoxin Reductase 2; D005978:Glutathione; D000094765:Glutathione Peroxidase GPX1