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This study investigated the impact of endogenous mtDNA on complement activation. mtDNA and nuclear DNA (nDNA) were extracted from human placental tissue and complement activation was determined using ELISA. When incubated in lepirudin-anticoagulated human blood and plasma, increasing concentrations of mtDNA, but not nDNA, resulted in dose- and time-dependent increases in C3bc, C3bBbP and soluble C5b-9 (sC5b-9). In a clinical context, mtDNA, nDNA, and complement levels of 55 resuscitated out-of-hospital cardiac arrest (OHCA) patients were determined using qPCR and ELISA. C3bc and sC5b-9 correlated significantly with mtDNA and nDNA in OHCA patients. We conclude that mtDNA, but not nDNA, triggers in vitro complement activation, which holds significance in a clinical context in OHCA patients. This novel mode of human complement activation might explain pathophysiological mechanisms of sterile inflammation and could be relevant for innovative therapeutic strategies.<\/jats:p>","DOI":"10.1038\/s41598-025-24705-1","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T10:49:05Z","timestamp":1763635745000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Extracellular mitochondrial DNA activates complement and is associated with complement activation in patients with out-of-hospital cardiac arrest"],"prefix":"10.1038","volume":"15","author":[{"given":"Eline","family":"de Boer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Lise","family":"Strandmoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Sokolova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trond M.","family":"Michelsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huy Q.","family":"Quach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktoriia","family":"Chaban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Espen R.","family":"Nakstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geir \u00d8.","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May-Kristin S.","family":"Torp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00e5re-Olav","family":"Stensl\u00f8kken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom E.","family":"Mollnes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2543-3251","authenticated-orcid":false,"given":"S\u00f8ren E.","family":"Pischke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"24705_CR1","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.3389\/fimmu.2018.01330","volume":"9","author":"M Vourc\u2019h","year":"2018","unstructured":"Vourc\u2019h, M., Roquilly, A. & Asehnoune, K. 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