Mitochondrial protection by the thioredoxin-2 and glutathione systems in an in vitro endothelial model of sepsis

Damon A. Lowes , Helen F Galley (1)

1 Academic Unit of Anaesthesia & Intensive Care

Oxidative stress and mitochondrial dysfunction are common features in patients with sepsis and organ failure. Within mitochondria, superoxide is converted to hydrogen peroxide by manganese containing superoxide dismutase (MnSOD) which is then detoxified by either the mitochondrial glutathione system, using the enzymes mitochondrial glutathione peroxidase-1 (mGPX-1), glutathione reductase (GRD) and the mitochondrial pool of glutathione (mGSH), or the thioredoxin-2 system, which uses the enzymes peroxiredoxin-3 (PRX-3) and thioredoxin reductase-2 (TRX-2R) and thioredoxin-2 (TRX-2). We investigated the relative contribution of these two systems, using selective inhibitors, in relation to mitochondrial dysfunction in endothelial cells cultured with lipopolysaccharide (LPS) and peptidoglycan (PepG). Specific inhibition of both the TRX-2 and mGSH systems increased intracellular total radical production (p<0.05) and reduced mitochondrial membrane potentials (p<0.05). Inhibition of 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 data 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.

Mots clés: Life Sciences

Damon A. Lowes, Helen F Galley. Mitochondrial protection by the thioredoxin-2 and glutathione systems in an in vitro endothelial model of sepsis. Biochemical Journal, 2011, 436 (1), pp.123-132. ⟨10.1042/BJ20102135⟩. ⟨hal-00591705⟩