{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:54:58Z","timestamp":1790718898164,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["RC2024"],"award-info":[{"award-number":["RC2024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Hydrogen sulfide (H2S) is a critical gasotransmitter that plays a dual role in physiological and pathological processes, particularly in the gastrointestinal tract. While physiological levels of H2S 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 H2S 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 \u00d7 10\u22127 M to 5 \u00d7 10\u22123 M on mitochondrial metabolism, redox balance, antioxidant defense, inflammatory responses, autophagy\/mitophagy, and apoptosis. Our results demonstrated a biphasic response: low-to-moderate H2S concentrations (1 \u00d7 10\u22127 M\u20131.5 \u00d7 10\u22123 M) enhance mitochondrial biogenesis through PGC-1\u03b1 activation, upregulating TFAM and COX-4 expression, and increasing the mtDNA copy number. In contrast, higher concentrations (2 \u00d7 10\u22123\u20135 \u00d7 10\u22123 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. H2S-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 H2S in intestinal cells, helping to develop new therapeutic approaches for gastrointestinal disorders.<\/jats:p>","DOI":"10.3390\/antiox14040384","type":"journal-article","created":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T05:35:03Z","timestamp":1742880903000},"page":"384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["The Dual Role of Exogenous Hydrogen Sulfide (H2S) in Intestinal Barrier Mitochondrial Function: Insights into Cytoprotection and Cytotoxicity Under Non-Stressed Conditions"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0629-0972","authenticated-orcid":false,"given":"Domenica","family":"Mallardi","sequence":"first","affiliation":[{"name":"Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4403-2317","authenticated-orcid":false,"given":"Guglielmina","family":"Chimienti","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Maqoud","sequence":"additional","affiliation":[{"name":"Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8255-4776","authenticated-orcid":false,"given":"Antonella","family":"Orlando","sequence":"additional","affiliation":[{"name":"Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7279-331X","authenticated-orcid":false,"given":"Simona","family":"Drago","sequence":"additional","affiliation":[{"name":"Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Malerba","sequence":"additional","affiliation":[{"name":"Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3929-3691","authenticated-orcid":false,"given":"Caterina","family":"De Virgilio","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1423-0774","authenticated-orcid":false,"given":"Hamid I.","family":"Akbarali","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0538-6072","authenticated-orcid":false,"given":"Francesco","family":"Russo","sequence":"additional","affiliation":[{"name":"Functional Gastrointestinal Disorders Research Group, National Institute of Gastroenterology IRCCS \u201cSaverio de Bellis\u201d, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9099","DOI":"10.3390\/molecules20059099","article-title":"Gaseous mediators nitric oxide and hydrogen sulfide in the mechanism of gastrointestinal integrity, protection and ulcer healing","volume":"20","author":"Magierowski","year":"2015","journal-title":"Molecules"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1096\/fj.12-216507","article-title":"Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics","volume":"27","author":"Coletta","year":"2013","journal-title":"FASEB J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1042\/bj2240591","article-title":"Interactions of sulfide and other ligands with cytochrome c oxidase. 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