Abstract
Dietary gliadin may show a broad spectrum of toxicity. The interplay between mitochondria and gliadin-induced oxidative stress has not been thoroughly examined in the intestinal epithelium. In this kinetic study, Caco-2 cells were exposed for 24 h to pepsin-trypsin-digested gliadin, alone or in combination with the antioxidant 2,6-di-tbutyl-p-cresol (BHT), and the effects on mitochondrial biogenesis and mtDNA were studied. Cells ability to recover from stress was determined after 24 h and 48 h of incubation in the culture medium. Gliadin-induced oxidative stress evoked a compensatory response. The stressor triggered a rapid and significant increase of Peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) and Peroxiredoxin III (PrxIII) proteins, and mtDNA amount. As for the effects of gliadin on mtDNA integrity, strand breaks, abasic sites, and modified bases were analyzed in three mtDNA regions. D-loop appeared a more fragile target than Ori-L and ND1/ND2. The temporal trend of the damage at D-loop paralleled that of the amount of mtDNA. Overall, a trend toward control values was shown 48 h after gliadin exposure. Finally, BHT was able to counteract the effects of gliadin. Results from this study highlighted the effects of gliadin-induced oxidative stress on mitochondria, providing valuable evidence that might improve the knowledge of the pathophysiology of gluten-related disorders.
Highlights
The complex of proteins called gluten contained in wheat gliadin, together with the homologous proteins from barley and rye, are responsible for a group of human diseases defined as “gluten-related disorders” (namely, autoimmune celiac disease (CD), allergy to wheat, and non-celiac gluten sensitivity (NCGS)) [1]
Results from this study highlighted the effects of gliadin-induced oxidative stress on mitochondria, providing valuable evidence that might improve the knowledge of the pathophysiology of gluten-related disorders
Cell viability in treated vs. untreated control cells was evaluated by the MTT test (Figure 1), which relies on the activities of the mitochondrial dehydrogenases
Summary
The complex of proteins called gluten contained in wheat gliadin, together with the homologous proteins from barley and rye, are responsible for a group of human diseases defined as “gluten-related disorders” (namely, autoimmune celiac disease (CD), allergy to wheat, and non-celiac gluten sensitivity (NCGS)) [1]. Immuno-toxic gliadin peptides can start both adaptive and innate immune responses leading to barrier disruption [3] and mucosal damage [4]. As for CD, gliadin might affect the pro-oxidant-antioxidant balance in the intestinal mucosa, far beyond the host’s capacity to quench [9,10]. Mitochondria, the alpha and omega of the major cell amount of ROS, play a crucial role in oxidative stress [11]. The molecular mechanism linking gluten toxicity with mitochondria, ROS, and inflammation could rely on the ability of mitochondrial ROS to activate the multi-protein caspase-1 activating complex (NLRP3 inflammasome) [15,16], as confirmed in peripheral blood mononuclear cells of celiac patients exposed to gliadin [17]
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