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Immunol."],"abstract":"<jats:p>Patients with occupational medicamentose-like dermatitis due to trichloroethylene often suffer from immune kidney injury. Our previous study reveals that C5b-9-dependent cytosolic Ca<jats:sup>2+<\/jats:sup> overload-induced ferroptosis is involved in trichloroethylene sensitized kidney injury. However, how C5b-9 causes cytosolic Ca<jats:sup>2+<\/jats:sup> rise and the specific mechanism whereby overloaded Ca<jats:sup>2+<\/jats:sup> induces ferroptosis remain unknown. The purpose of our study was to explore the role of IP3R-dependent mitochondrial dysfunction in C5b-9 mediated ferroptosis in trichloroethylene sensitized kidney. Our results showed that IP3R was activated, and mitochondrial membrane potential was decreased in the renal epithelial cells of trichloroethylene-sensitized mice, and these changes were antagonized by CD59, a C5b-9 inhibitory protein. Moreover, this phenomenon was reproduced in a C5b-9-attacked HK-2 cell model. Further investigation showed that RNA interference with <jats:italic>IP3R<\/jats:italic> not only alleviated C5b-9-induced cytosolic Ca<jats:sup>2+<\/jats:sup> overload and mitochondrial membrane potential loss but also attenuated C5b-9-induced ferroptosis in HK-2 cells. Mechanistically, IP3R-dependent cytosolic Ca<jats:sup>2+<\/jats:sup> overload activated the mitochondrial permeability transition pore, resulting in the loss of mitochondrial membrane potential and ferroptosis of HK-2 cells. Finally, cyclosporin A, a mitochondrial permeability transition pore inhibitor, not only ameliorated IP3R-dependent mitochondrial dysfunction but also blocked C5b-9-induced ferroptosis. Taken together, these results suggest that IP3R-dependent mitochondrial dysfunction plays an important role in trichloroethylene sensitized renal tubular ferroptosis.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1106693","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T04:31:23Z","timestamp":1686630683000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["IP3R-dependent mitochondrial dysfunction mediates C5b-9-induced ferroptosis in trichloroethylene-caused immune kidney injury"],"prefix":"10.3389","volume":"14","author":[{"given":"Zhibing","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinru","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xulei","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qixing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2022.116176","article-title":"Oral ingestion of the environmental toxicant trichloroethylene in rats induces alterations in the gut microbiome: relevance to idiopathic parkinson\u2019s disease","volume":"451","author":"Ilieva","year":"2022","journal-title":"Toxicol Appl Pharmacol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.1205879","article-title":"Human health effects of trichloroethylene: key findings and scientific issues","volume":"121","author":"Chiu","year":"2013","journal-title":"Environ Health Perspect"},{"key":"B3","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.mrrev.2014.04.003","article-title":"Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity","volume":"762","author":"Lash","year":"2014","journal-title":"Mutat Res Rev Mutat Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.116.232629","article-title":"Target organ metabolism, toxicity, and mechanisms of trichloroethylene and perchloroethylene: key similarities, differences, and data gaps","volume":"359","author":"Cichocki","year":"2016","journal-title":"J Pharmacol Exp Ther"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1346-8138.2010.01155.x","article-title":"Hypersensitivity syndrome due to trichloroethylene exposure: a severe generalized skin reaction resembling drug-induced hypersensitivity syndrome","volume":"38","author":"Watanabe","year":"2011","journal-title":"J Dermatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-022-03326-x","article-title":"Increased serum anti-CYP2E1 IgG autoantibody levels may be involved in the pathogenesis of occupational trichloroethylene hypersensitivity syndrome: a case-control study","volume":"96","author":"Nakajima","year":"2022","journal-title":"Arch Toxicol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/1348-9585.12142","article-title":"Trichloroethylene and trichloroethanol induce skin sensitization with focal hepatic necrosis in guinea pigs","volume":"62","author":"Zhao","year":"2020","journal-title":"J Occup. 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