The Dual Role of Exogenous Hydrogen Sulfide (H(2)S) in Intestinal Barrier Mitochondrial Function: Insights into Cytoprotection and Cytotoxicity Under Non-Stressed Conditions.

Hydrogen sulfide (H(2)S) is a critical gasotransmitter that plays a dual role in physiological and pathological processes, particularly in the gastrointestinal tract. While physiological levels of H(2)S exert cytoprotective effects, excessive concentrations can lead to toxicity, oxidative stress, and inflammation. The aim of this study was to investigate the dose-dependent effects of exogenous H(2)S on mitochondrial functions and biogenesis in intestinal epithelial cells under non-stressed conditions. Using a Caco-2 monolayer model, we evaluated the impact of sodium hydrosulfide (NaHS) at concentrations ranging from 1 × 10(-7) M to 5 × 10(-3) M on mitochondrial metabolism, redox balance, antioxidant defense, inflammatory responses, autophagy/mitophagy, and apoptosis. Our results demonstrated a biphasic response: low-to-moderate H(2)S concentrations (1 × 10(-7) M-1.5 × 10(-3) M) enhance mitochondrial biogenesis through PGC-1α activation, upregulating TFAM and COX-4 expression, and increasing the mtDNA copy number. In contrast, higher concentrations (2 × 10(-3)-5 × 10(-3) M) impair mitochondrial function, induce oxidative stress, and promote apoptosis. These effects are associated with elevated reactive oxygen species (ROS) production, dysregulation of antioxidant enzymes, and COX-2-mediated inflammation. H(2)S-induced autophagy/mitophagy is a protective mechanism at intermediate concentrations but fails to mitigate mitochondrial damage at toxic levels. This study underscores the delicate balance between the cytoprotective and cytotoxic effects of exogenous H(2)S in intestinal cells, helping to develop new therapeutic approaches for gastrointestinal disorders.