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Mitochondria constitute about 30 percent of the human heart. Mitochondrial DNA (mtDNA) is a damage\u2010associated\u2010molecular\u2010pattern that induce injurious sterile inflammation. Little is known about mtDNA's inflammatory signalling pathways in cardiomyocytes and how mtDNA is internalized to associate with its putative receptor, toll\u2010like receptor 9 (TLR9).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We hypothesized that mtDNA can be internalized in cardiomyocytes and induce an inflammatory response. Adult mouse cardiomyocytes were exposed to hypoxia\u2010reoxygenation and extracellular DNA. Microscale thermophoresis was used to demonstrate binding between nucleolin and DNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results<\/jats:title><jats:p>Expression of the pro\u2010inflammatory cytokines IL\u20101\u03b2 and TNF\u03b1 were upregulated by mtDNA, but not by nuclear DNA (nDNA), in cardiomyocytes exposed to hypoxia\u2010reoxygenation. Blocking the RNA\/DNA binding protein nucleolin with midkine reduced expression of IL\u20101\u03b2\/TNF\u03b1 and the nucleolin inhibitor AS1411 reduced interleukin\u20106 release in adult mouse cardiomyocytes. mtDNA bound 10\u2010fold stronger than nDNA to nucleolin. In HEK293\u2010NF\u2010\u03baB reporter cells, mtDNA induced NF\u2010\u03baB activity in normoxia, while CpG\u2010DNA and hypoxia\u2010reoxygenation, synergistically induced TLR9\u2010dependent NF\u2010\u03baB activity. Protein expression of nucleolin was found in the plasma membrane of cardiomyocytes and inhibition of nucleolin with midkine inhibited cellular uptake of CpG\u2010DNA. Inhibition of endocytosis did not reduce CpG\u2010DNA uptake in cardiomyocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and implications<\/jats:title><jats:p>mtDNA, but not nDNA, induce an inflammatory response in mouse cardiomyocytes during hypoxia\u2010reoxygenation. In cardiomyocytes, nucleolin is expressed on the membrane and blocking nucleolin reduce inflammation. Nucleolin might be a therapeutic target to prevent uptake of immunogenic DNA and reduce inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v176.22\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v176.22\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14830","type":"journal-article","created":{"date-parts":[[2019,8,14]],"date-time":"2019-08-14T17:18:53Z","timestamp":1565803133000},"page":"4360-4372","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation"],"prefix":"10.1111","volume":"176","author":[{"given":"Lars Henrik","family":"Mariero","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Division of Physiology, Institute of Basic Medical Sciences, Faculty of Medicine University of Oslo  Oslo 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