{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T22:32:09Z","timestamp":1768689129222,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,24]]},"group-title":"Cell Biology","reference-count":64,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["GM130183"],"award-info":[{"award-number":["GM130183"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM134964"],"award-info":[{"award-number":["R35GM134964"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  O\n                  <jats:sub>2<\/jats:sub>\n                  sensing by hypoxia-inducible factor (HIF) is a principal mechanism by which aerobic organisms adjust cellular energy metabolism and adapt to O\n                  <jats:sub>2<\/jats:sub>\n                  limitation. In this study, we show that H\n                  <jats:sub>2<\/jats:sub>\n                  S, a product of host and microbial metabolism, profoundly influences the threshold for HIF-dependent hypoxia-sensing by increasing intracellular O\n                  <jats:sub>2<\/jats:sub>\n                  . The dose-dependent destabilization of HIF by H\n                  <jats:sub>2<\/jats:sub>\n                  S is inversely correlated with sulfide quinone oxidoreductase, which oxidizes sulfide in the mitochondrion. Hypoxia sensors provide a quantitative estimate of the magnitude of H\n                  <jats:sub>2<\/jats:sub>\n                  S-induced perturbation. The O\n                  <jats:sub>2<\/jats:sub>\n                  concentration in cells grown in a 2% O\n                  <jats:sub>2<\/jats:sub>\n                  atmosphere is sensed as 5 or 15 % O\n                  <jats:sub>2<\/jats:sub>\n                  in the presence of 25 or 100 ppm H\n                  <jats:sub>2<\/jats:sub>\n                  S, respectively. Sustained exposure to H\n                  <jats:sub>2<\/jats:sub>\n                  S elicits the hallmarks of hyperoxia-associated cytotoxicity, including loss of Fe-S proteins in cellular and murine models. H\n                  <jats:sub>2<\/jats:sub>\n                  S thus emerges as a powerful regulator of O\n                  <jats:sub>2<\/jats:sub>\n                  sensing and signaling with possible implications for dysregulation in O\n                  <jats:sub>2<\/jats:sub>\n                  toxicity diseases.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    The mitochondrial electron transport chain (ETC) accounts for \u223c90% of whole body O\n                    <jats:sub>2<\/jats:sub>\n                    consumption. However, our understanding of how metabolites modify ETC flux and therefore, intracellular O\n                    <jats:sub>2<\/jats:sub>\n                    availability, are poor. In this study, we demonstrate that hydrogen sulfide (H\n                    <jats:sub>2<\/jats:sub>\n                    S), which is produced by host and gut microbes alike, increases intracellular O\n                    <jats:sub>2<\/jats:sub>\n                    by decreasing ETC flux, and destabilizes the principal hypoxia sensor, HIF-1\u03b1. The upshift in intracellular O\n                    <jats:sub>2<\/jats:sub>\n                    levels is quantitatively significant, such that 2% O\n                    <jats:sub>2<\/jats:sub>\n                    is sensed as 5-15% O\n                    <jats:sub>2<\/jats:sub>\n                    at varying H\n                    <jats:sub>2<\/jats:sub>\n                    S concentrations, with concomitant destabilization of Fe-S proteins, a signature of cellular hyperoxia. Our study identifies H\n                    <jats:sub>2<\/jats:sub>\n                    S as a HIF-1\u03b1 regulator with important implications for the large class of mitochondrial diseases characterized by dysregulated O\n                    <jats:sub>2<\/jats:sub>\n                    metabolism.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.24.666576","type":"posted-content","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T18:30:10Z","timestamp":1753381810000},"source":"Crossref","is-referenced-by-count":0,"title":["Hydrogen sulfide increases intracellular oxygen and regulates the HIF response"],"prefix":"10.64898","author":[{"given":"Joseph","family":"Brake","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0726-8707","authenticated-orcid":false,"given":"David A","family":"Hanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roshan","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianni","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron P.","family":"Landry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rashi","family":"Singhal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eranthie","family":"Weerapana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yatrik M.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruma","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025072604201099000_2025.07.24.666576v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1118439"},{"key":"2025072604201099000_2025.07.24.666576v1.2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.07.020"},{"key":"2025072604201099000_2025.07.24.666576v1.3","first-page":"1","article-title":"Partial pressure of oxygen in the human body: a general review","volume":"9","year":"2019","journal-title":"Am J Blood Res"},{"key":"2025072604201099000_2025.07.24.666576v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2011.01258.x"},{"key":"2025072604201099000_2025.07.24.666576v1.5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.3.1230"},{"key":"2025072604201099000_2025.07.24.666576v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059817"},{"key":"2025072604201099000_2025.07.24.666576v1.7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059796"},{"key":"2025072604201099000_2025.07.24.666576v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/20459"},{"key":"2025072604201099000_2025.07.24.666576v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/35017054"},{"key":"2025072604201099000_2025.07.24.666576v1.10","doi-asserted-by":"crossref","unstructured":"P. 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