{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T12:16:52Z","timestamp":1784809012286,"version":"3.55.0"},"reference-count":44,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,12,15]]},"abstract":"<jats:p>The redox status of the extracellular compartment has only just been elucidated as a mechanism controlling intracellular signal transduction and correlates with aging, diabetes, heart disease and lung fibrosis. In the present paper, we describe a mechanism by which oxidizing extracellular environments, as maintained by the cysteine\/cystine (Cys\/CySS) redox couple, induce mitochondria-derived ROS (reactive oxygen species) generation and cause the activation of Nrf2 (nuclear factor-erythroid 2-related factor 2), inducing an antioxidant response. NIH 3T3 cells were cultured in medium with extracellular Cys\/CySS redox potentials (Eh), ranging from 0 to \u2212150 mV. Cellular and mitochondrial ROS production significantly increased in cells incubated under more oxidizing extracellular conditions (0 and \u221246 mV). Trx2 (thioredoxin-2) is a mitochondrial-specific oxidoreductase and antioxidant and became oxidized in cells incubated at 0 or \u221246 mV. MEFs (mouse embryonic fibroblasts) from Trx2-overexpressing transgenic (Trx2 Tg) mice produced less intracellular ROS compared with WT (wild-type) MEFs at the more oxidizing extracellular conditions. Nrf2 activity was increased in WT MEFs at the 0 or \u221246 mV conditions, but was inhibited in Trx2 Tg MEFs under the same conditions. Furthermore, Nrf2-regulated gene expression was significantly increased in the WT MEFs, but not in the Trx2 Tg MEFs. These results show that the Cys\/CySS redox status in the extracellular compartment regulates intracellular ROS generated primarily in the mitochondria, which play an important role in the activation of Nrf2 and up-regulation of antioxidant and detoxification systems.<\/jats:p>","DOI":"10.1042\/bj20091286","type":"journal-article","created":{"date-parts":[[2009,10,1]],"date-time":"2009-10-01T10:15:10Z","timestamp":1254392110000},"page":"491-500","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Extracellular redox status regulates Nrf2 activation through mitochondrial reactive oxygen species"],"prefix":"10.1042","volume":"424","author":[{"given":"Barry\u00a0R.","family":"Imhoff","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy\/Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory School of Medicine, Emory University, Atlanta, GA 30322, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason\u00a0M.","family":"Hansen","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy\/Immunology, Cystic Fibrosis and Sleep, Department of Pediatrics, Emory School of Medicine, Emory University, Atlanta, GA 30322, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2009,12,10]]},"reference":[{"key":"2021112214264951900_B1","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/j.bbagen.2008.01.011","article-title":"Redox compartmentalization in eukaryotic cells","volume":"1780","author":"Go","year":"2008","journal-title":"Biochim. 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