{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:52:29Z","timestamp":1790866349804,"version":"4.1.0"},"reference-count":42,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,1,15]]},"abstract":"<jats:p>8-Nitro-cGMP (8-nitroguanosine 3\u2032,5\u2032-cyclic monophosphate) is a nitrated derivative of cGMP, which can function as a unique electrophilic second messenger involved in regulation of an antioxidant adaptive response in cells. In the present study, we investigated chemical and biochemical regulatory mechanisms involved in 8-nitro-cGMP formation, with particular focus on the roles of ROS (reactive oxygen species). Chemical analyses demonstrated that peroxynitrite-dependent oxidation and myeloperoxidase-dependent oxidation of nitrite in the presence of H2O2 were two major pathways for guanine nucleotide nitration. Among the guanine nucleotides examined, GTP was the most sensitive to peroxynitrite-mediated nitration. Immunocytochemical and tandem mass spectrometric analyses revealed that formation of 8-nitro-cGMP in rat C6 glioma cells stimulated with lipopolysaccharide plus pro-inflammatory cytokines depended on production of both superoxide and H2O2. Using the mitochondria-targeted chemical probe MitoSOX\u2122 Red, we found that mitochondria-derived superoxide can act as a direct determinant of 8-nitro-cGMP formation. Furthermore, we demonstrated that Nox2 (NADPH oxidase 2)-generated H2O2 regulated mitochondria-derived superoxide production, which suggests the importance of cross-talk between Nox2-dependent H2O2 production and mitochondrial superoxide production. The results of the present study suggest that 8-nitro-cGMP can serve as a unique second messenger that may be implicated in regulating ROS signalling in the presence of NO.<\/jats:p>","DOI":"10.1042\/bj20111130","type":"journal-article","created":{"date-parts":[[2011,10,5]],"date-time":"2011-10-05T04:21:39Z","timestamp":1317788499000},"page":"719-730","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Regulation by mitochondrial superoxide and NADPH oxidase of cellular formation of nitrated cyclic GMP: potential implications for ROS signalling"],"prefix":"10.1042","volume":"441","author":[{"given":"Khandaker\u00a0Ahtesham","family":"Ahmed","sequence":"first","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Sawa","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan"},{"name":"PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-001, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideshi","family":"Ihara","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Kasamatsu","sequence":"additional","affiliation":[{"name":"Department of Biological Science, Graduate School of Science, Osaka Prefecture University, 1-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yoshitake","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md.\u00a0Mizanur","family":"Rahaman","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigemoto","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Akaike","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2011,12,21]]},"reference":[{"key":"2021112215261090000_B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1172\/JCI112536","article-title":"Cyclic guanosine monophosphate as a mediator of vasodilation","volume":"78","author":"Murad","year":"1986","journal-title":"J. Clin. Invest."},{"key":"2021112215261090000_B2","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0031-6997(24)01457-1","article-title":"Guanylyl cyclases and signaling by cyclic GMP","volume":"52","author":"Lucas","year":"2000","journal-title":"Pharmacol. Rev."},{"key":"2021112215261090000_B3","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/nchembio.2007.33","article-title":"Protein S-guanylation by the biological signal 8-nitroguanosine 3\u2032,5\u2032-cyclic monophosphate","volume":"3","author":"Sawa","year":"2007","journal-title":"Nat. Chem. Biol."},{"key":"2021112215261090000_B4","doi-asserted-by":"crossref","first-page":"3746","DOI":"10.4049\/jimmunol.0803363","article-title":"Cytoprotective function of heme oxygenase 1 induced by a nitrated cyclic nucleotide formed during murine salmonellosis","volume":"182","author":"Zaki","year":"2009","journal-title":"J. Immunol."},{"key":"2021112215261090000_B5","doi-asserted-by":"crossref","first-page":"23970","DOI":"10.1074\/jbc.M110.145441","article-title":"The critical role of nitric oxide signaling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response","volume":"285","author":"Fujii","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2021112215261090000_B6","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.niox.2011.04.015","article-title":"Methodological proof of immunocytochemistry for specific identification of 8-nitroguanosine 3\u2032,5\u2032-cyclic monophosphate formed in glia cells","volume":"25","author":"Ihara","year":"2011","journal-title":"Nitric Oxide"},{"key":"2021112215261090000_B7","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.niox.2010.06.006","article-title":"Cell signaling mediated by nitrated cyclic guanine nucleotide","volume":"23","author":"Akaike","year":"2010","journal-title":"Nitric Oxide"},{"key":"2021112215261090000_B8","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s00726-010-0535-1","article-title":"Protein cysteine S-guanylation and electrophilic signal transduction by endogenous nitro-nucleotides","volume":"41","author":"Ahmed","year":"2011","journal-title":"Amino Acids"},{"key":"2021112215261090000_B9","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/nchembio1107-687","article-title":"Nitrated cyclic GMP as a new cellular signal","volume":"3","author":"Feelisch","year":"2007","journal-title":"Nat. Chem. Biol."},{"key":"2021112215261090000_B10","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.niox.2005.06.005","article-title":"Nitrative DNA damage in inflammation and its possible role in carcinogenesis","volume":"14","author":"Sawa","year":"2006","journal-title":"Nitric Oxide"},{"key":"2021112215261090000_B11","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.niox.2005.11.001","article-title":"Peroxynitrite-induced oxidation and nitration products of guanine and 8-oxoguanine: structures and mechanisms of product formation","volume":"14","author":"Niles","year":"2006","journal-title":"Nitric Oxide"},{"key":"2021112215261090000_B12","doi-asserted-by":"crossref","first-page":"6884","DOI":"10.1016\/S0021-9258(18)68727-7","article-title":"Superoxide dismutase and catalase conjugated to polyethylene glycol increases endothelial enzyme activity and oxidant resistance","volume":"263","author":"Beckman","year":"1988","journal-title":"J. Biol. Chem."},{"key":"2021112215261090000_B13","first-page":"666","article-title":"Tumor-targeting chemotherapy by a xanthine oxidase-polymer conjugate that generates oxygen-free radicals in tumor tissue","volume":"60","author":"Sawa","year":"2000","journal-title":"Cancer Res."},{"key":"2021112215261090000_B14","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/S0076-6879(96)69030-2","article-title":"Syntheses of peroxynitrite: to go with the flow or on solid grounds?","volume":"269","author":"Koppenol","year":"1996","journal-title":"Methods Enzymol."},{"key":"2021112215261090000_B15","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3109\/10715769209061085","article-title":"The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein","volume":"17","author":"Darley-Usmar","year":"1992","journal-title":"Free Radical Res. Commun."},{"key":"2021112215261090000_B16","doi-asserted-by":"crossref","first-page":"7617","DOI":"10.1074\/jbc.272.12.7617","article-title":"Formation of reactive nitrogen species during peroxidase-catalyzed oxidation of nitrite. A potential additional mechanism of nitric oxide-dependent toxicity","volume":"272","author":"van der Vliet","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021112215261090000_B17","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/34923","article-title":"Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils","volume":"391","author":"Eiserich","year":"1998","journal-title":"Nature"},{"key":"2021112215261090000_B18","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1021\/tx980207u","article-title":"Nitration of unsaturated fatty acids by nitric oxide-derived reactive nitrogen species peroxynitrite, nitrous acid, nitrogen dioxide, and nitronium ion","volume":"12","author":"O'Donnell","year":"1999","journal-title":"Chem. Res. Toxicol."},{"key":"2021112215261090000_B19","doi-asserted-by":"crossref","first-page":"32467","DOI":"10.1074\/jbc.M910169199","article-title":"Tyrosine nitration by peroxynitrite formed from nitric oxide and superoxide generated by xanthine oxidase","volume":"275","author":"Sawa","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021112215261090000_B20","doi-asserted-by":"crossref","first-page":"19199","DOI":"10.1074\/jbc.271.32.19199","article-title":"Formation of nitrating and chlorinating species by reaction of nitrite with hypochlorous acid. A novel mechanism for nitric oxide-mediated protein modification","volume":"271","author":"Eiserich","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021112215261090000_B21","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1111\/j.1471-4159.2007.04502.x","article-title":"Mutant SOD1induced neuronal toxicity is mediated by increased mitochondrial superoxide levels","volume":"102","author":"Zimmerman","year":"2007","journal-title":"J. Neurochem."},{"key":"2021112215261090000_B22","doi-asserted-by":"crossref","first-page":"11596","DOI":"10.1074\/jbc.M109.076984","article-title":"Trypanosoma cruzi induces the reactive oxygen species-PARP-1-RelA pathway for up-regulation of cytokine expression in cardiomyocytes","volume":"285","author":"Ba","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2021112215261090000_B23","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1002\/jcp.21402","article-title":"Effect of dihydrotestosterone on hydrogen peroxide-induced apoptosis of mouse embryonic stem cells","volume":"216","author":"Lee","year":"2008","journal-title":"J. Cell. Physiol."},{"key":"2021112215261090000_B24","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/sj.bjp.0701809","article-title":"Inhibition of nitrergic neurotransmission in the bovine retractor penis muscle by an oxidant stress: effects of superoxide dismutase mimetics","volume":"124","author":"Mok","year":"1998","journal-title":"Br. J. Pharmacol."},{"key":"2021112215261090000_B25","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cell.2005.02.001","article-title":"Mitochondria, oxidants, and aging","volume":"120","author":"Balaban","year":"2005","journal-title":"Cell"},{"key":"2021112215261090000_B26","doi-asserted-by":"crossref","first-page":"8516","DOI":"10.1074\/jbc.M210432200","article-title":"Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production","volume":"278","author":"Li","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021112215261090000_B27","first-page":"217","article-title":"NADPH oxidase and mitochondrial ROS are involved in the TNF-\u03b1induced vascular cell adhesion molecule-1 and monocyte adhesion in cultured endothelial cells","volume":"10","author":"Yu","year":"2006","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"2021112215261090000_B28","doi-asserted-by":"crossref","first-page":"3249","DOI":"10.1111\/j.1742-4658.2008.06488.x","article-title":"Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species","volume":"275","author":"Sumimoto","year":"2008","journal-title":"FEBS J."},{"key":"2021112215261090000_B29","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S0891-5849(98)00095-1","article-title":"Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide","volume":"25","author":"Squadrito","year":"1998","journal-title":"Free Radical Biol. Med."},{"key":"2021112215261090000_B30","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1021\/tx960046z","article-title":"Carbon dioxide: physiological catalyst for peroxynitrite-mediated cellular damage or cellular protectant?","volume":"9","author":"Lymar","year":"1996","journal-title":"Chem. Res. Toxicol."},{"key":"2021112215261090000_B31","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0898-8838(08)60194-4","article-title":"Reduction potentials involving inorganic free radicals in aqueous solution","volume":"33","author":"Stanbury","year":"1989","journal-title":"Adv. Inorg. Chem."},{"key":"2021112215261090000_B32","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1063\/1.555843","article-title":"Reduction potentials of one-electron couples involving free radicals in aqueous solution","volume":"18","author":"Wardman","year":"1989","journal-title":"J. Phys. Chem. Ref. Data"},{"key":"2021112215261090000_B33","first-page":"477","article-title":"Electron transfer reaction rates and equilibria of the carbonate and sulfate radical anions","volume":"38","author":"Huie","year":"1991","journal-title":"Radiat. Phys. Chem."},{"key":"2021112215261090000_B34","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1021\/ja962255b","article-title":"How easily oxidizable is DNA? One-electron reduction potentials of adenosine and guanosine radicals in aqueous solution","volume":"119","author":"Steenken","year":"1997","journal-title":"J. Am. Chem. Soc."},{"key":"2021112215261090000_B35","doi-asserted-by":"crossref","first-page":"20597","DOI":"10.1074\/jbc.M000181200","article-title":"Mechanism of reaction of myeloperoxidase with nitrite","volume":"275","author":"Burner","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021112215261090000_B36","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/S0006-291X(02)03075-9","article-title":"Redox properties of the couples compound I\/compound II and compound II\/native enzyme of human myeloperoxidase","volume":"301","author":"Furtmuller","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112215261090000_B37","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1006\/abbi.2001.2674","article-title":"Redox intermediates of plant and mammalian peroxidases: a comparative transient-kinetic study of their reactivity toward indole derivatives","volume":"398","author":"Jantschko","year":"2002","journal-title":"Arch. Biochem. Biophys."},{"key":"2021112215261090000_B38","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1146\/annurev.bi.63.070194.000533","article-title":"Structure and function of G protein-coupled receptors","volume":"63","author":"Strader","year":"1994","journal-title":"Annu. Rev. Biochem."},{"key":"2021112215261090000_B39","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/S1089-8603(02)00117-9","article-title":"Peroxynitrite activates NF-E2-related factor 2\/antioxidant response element through the pathway of phosphatidylinositol 3-kinase: the role of nitric oxide synthase in rat glutathione S-transferase A2 induction","volume":"7","author":"Kang","year":"2002","journal-title":"Nitric Oxide"},{"key":"2021112215261090000_B40","doi-asserted-by":"crossref","first-page":"e23211","DOI":"10.1371\/journal.pone.0023211","article-title":"Mitochondrial network determines intracellular ROS dynamics and sensitivity to oxidative stress through switching inter-mitochondrial messengers","volume":"6","author":"Park","year":"2011","journal-title":"PLoS ONE"},{"key":"2021112215261090000_B41","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.cellsig.2007.11.013","article-title":"Local production of O2\u2212 by NAD(P)H oxidase in the sarcoplasmic reticulum of coronary arterial myocytes: cADPR-mediated Ca2+ regulation","volume":"20","author":"Zhang","year":"2008","journal-title":"Cell. Signalling"},{"key":"2021112215261090000_B42","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1111\/j.1476-5381.2011.01201.x","article-title":"Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice","volume":"162","author":"Tokutomi","year":"2011","journal-title":"Br. J. Pharmacol."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/441\/2\/719\/639634\/bj4410719.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/441\/2\/719\/639634\/bj4410719.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T09:08:50Z","timestamp":1741770530000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/441\/2\/719\/45899\/Regulation-by-mitochondrial-superoxide-and-NADPH"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,12,21]]},"references-count":42,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2012,1,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20111130","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,12,21]]}}}