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

Area of Science:

• Cell Biology
• Oxidative Stress Research
• Gastrointestinal Physiology

Background:

• Oxidative stress damages intestinal epithelial cells, compromising tight junctions and leading to systemic stress.
• The SIRT1/PGC-1α pathway is linked to oxidative damage, but its role in autophagy/mitophagy-mediated protection of intestinal cells is unclear.

Purpose of the Study:

• To investigate the SIRT1/PGC-1α pathway's role in regulating autophagy/mitophagy and tight junction proteins in porcine intestinal epithelial cells (IPEC-1) under oxidative stress.
• To elucidate the protective mechanisms against oxidative stress-induced intestinal dysfunction.

Main Methods:

• IPEC-1 cells were exposed to hydrogen peroxide (H₂O₂) to induce oxidative stress.
• SIRT1 activator (SRT 1720) and inhibitor (EX 527) were used to modulate the SIRT1/PGC-1α pathway.
• Levels of reactive oxygen species (ROS), mitochondrial membrane potential, COX IV mRNA, autophagy/mitophagy markers, and tight junction proteins were assessed.

Main Results:

• H₂O₂ exposure increased ROS, decreased mitochondrial potential, and inhibited tight junction molecules, while suppressing SIRT1/PGC-1α. Autophagy and mitophagy were activated.
• SRT 1720 activated SIRT1/PGC-1α, enhancing autophagy/mitophagy, reducing ROS, increasing mitochondrial potential and COX IV expression.
• EX 527 reversed the effects of SRT 1720, confirming SIRT1's role. SIRT1 activation significantly upregulated tight junction proteins.

Conclusions:

• SIRT1/PGC-1α pathway activation promotes autophagy/mitophagy, which protects intestinal epithelial cells against oxidative stress.
• This protective mechanism involves reducing ROS production and restoring mitochondrial function.
• Upregulation of tight junction proteins by SIRT1/PGC-1α activation is crucial for maintaining intestinal barrier integrity under oxidative stress.