Inhibition of thioredoxin 2 by intracellular methylglyoxal accumulation leads to mitochondrial dysfunction and apoptosis in INS-1 cells

Bisdemethoxycurcumin is one of the three curcuminoids of turmeric and exhibits good antioxidant activity in animal models. This study is aimed at investigating the effect of bisdemethoxycurcumin on small intestinal mitochondrial dysfunction in lipopolysaccharide- (LPS-) treated broilers, especially on the mitochondrial thioredoxin 2 system and mitochondrial biogenesis. A total of 320 broiler chickens were randomly assigned into four experimental diets using a 2 × 2 factorial arrangement with diet (0 and 150 mg/kg bisdemethoxycurcumin supplementation) and stress (saline or LPS challenge) for 20 days. Broilers received a dose of LPS (1 mg/kg body weight) or sterile saline intraperitoneally on days 16, 18, and 20 of the trial. Bisdemethoxycurcumin mitigated the mitochondrial dysfunction of jejunum and ileum induced by LPS, as evident by the reduced reactive oxygen species levels and the increased mitochondrial membrane potential. Bisdemethoxycurcumin partially reversed the decrease in the mitochondrial DNA copy number and the depletion of ATP levels. Bisdemethoxycurcumin activated the mitochondrial antioxidant response, including the prevention of lipid peroxidation, enhancement of manganese superoxide dismutase activity, and the upregulation of the mitochondrial glutaredoxin 5 and thioredoxin 2 system. The enhanced mitochondrial respiratory complex activities in jejunum and ileum were also attributed to bisdemethoxycurcumin treatment. In addition, bisdemethoxycurcumin induced mitochondrial biogenesis via transcriptional regulation of proliferator-activated receptor-gamma coactivator-1alpha pathway. In conclusion, our results demonstrated the potential of bisdemethoxycurcumin to attenuate small intestinal mitochondrial dysfunction, which might be mediated via activating the mitochondrial antioxidant system and mitochondrial biogenesis in LPS-treated broilers.

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

Biochemical Journal ◽

10.1042/bj20102135 ◽

2011 ◽

Vol 436 (1) ◽

pp. 123-132 ◽

Cited By ~ 24

Author(s):

Damon A. Lowes ◽

Helen F. Galley

Keyword(s):

Endothelial Cells ◽

Mitochondrial Dysfunction ◽

Lactate Production ◽

Thioredoxin Reductase ◽

Low Oxygen ◽

Atp Production ◽

Relative Contribution ◽

Mitochondrial Glutathione ◽

Thioredoxin 2

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.

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