SIRT1/PGC-1 pathway activation triggers autophagy/mitophagy and attenuates oxidative damage in intestinal epithelial cells

Oxidative stress leads to intestinal epithelial cells damage, which induces tight junction injury and systemic endogenous stress syndrome. The evidence suggests that SIRT1/PGC-1 alpha pathway is closely associated with oxidative damage. However, the mechanism in protecting intestinal epithelial cells against oxidative stress dependant on autopahgy/mitophagy remains to be elucidated. In the current study, we investigated the functional role of SIRT1/PGC-1 alpha pathway on regulation of autopahgy/mitophagy and tight junction protein expression underlying the oxidative dysfunction in porcine intestinal epithelial cells (IPEC-1). Results demonstrated that H2O2 exposure caused high accumulation of ROS, with a decrease of mitochondrial membrane potential and an inhibition of the tight junction molecules in IPEC-1 cells. Also, COX IV mRNA expression and SIRT1/PGC-1 alpha pathway were suppressed. Autophagy and PINK1/Parkin dependant-mitophagy were activated following H2O2 treatment. Further research indicated that activation of SIRT1/PGC-1 alpha pathway caused by specific activator SRT 1720 resulted in elevating autophagy/mitophagy related markers and SIRT1 inhibitor EX 527 reversed these effects. Additionally, SIRT1 activation significantly suppressed the ROS generation, leading to increase mitochondrial membrane potential and COX IV expression. Most importantly, the expression of tight junction molecules contributing to maintain intestinal barrier integrity was significantly up-regulated. Collectively, these findings indicated that autophagy/mitophagy elevation caused by SIRT1/PGC-1 alpha pathway activation might be a protective mechanism to increase tight junction integrity against oxidative stress-mediated ROS production in IPEC-1 cells. (C) 2019 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.