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

Damon A Lowes, Helen F Galley

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27 Citations (Scopus)

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 preventingmitochondrial dysfunction than the mGSH system in endothelial cells under conditions that mimic a septic insult.
Original languageEnglish
Pages (from-to)123-132
Number of pages10
JournalBiochemical Journal
Volume436
Issue number1
Early online date28 Feb 2011
DOIs
Publication statusPublished - 15 May 2011

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Keywords

  • animals
  • endothelial Cells
  • glutathione
  • glutathione Peroxidase
  • glutathione Reductase
  • humans
  • membrane potential, mitochondrial
  • mice
  • mitochondria
  • peroxiredoxin III
  • sepsis
  • thioredoxin reductase 2
  • thioredoxins

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