{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T15:15:27Z","timestamp":1778598927506,"version":"3.51.4"},"reference-count":58,"publisher":"American Physiological Society","issue":"3","funder":[{"DOI":"10.13039\/501100005366","name":"University of Oslo","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005366","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005416","name":"Norwegian Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2015,8,1]]},"abstract":"<jats:p> Cardiac mitochondrial dysfunction has been implicated in heart failure of diverse etiologies. Generalized mitochondrial disease also leads to cardiomyopathy with various clinical manifestations. Impaired mitochondrial homeostasis may over time, such as in the aging heart, lead to cardiac dysfunction. Mitochondrial DNA (mtDNA), close to the electron transport chain and unprotected by histones, may be a primary pathogenetic site, but this is not known. Here, we test the hypothesis that cumulative damage of cardiomyocyte mtDNA leads to cardiomyopathy and heart failure. Transgenic mice with Tet-on inducible, cardiomyocyte-specific expression of a mutant uracil-DNA glycosylase 1 (mutUNG1) were generated. The mutUNG1 is known to remove thymine in addition to uracil from the mitochondrial genome, generating apyrimidinic sites, which obstruct mtDNA function. Following induction of mutUNG1 in cardiac myocytes by administering doxycycline, the mice developed hypertrophic cardiomyopathy, leading to congestive heart failure and premature death after \u223c2 mo. The heart showed reduced mtDNA replication, severely diminished mtDNA transcription, and suppressed mitochondrial respiration with increased Pgc-1\u03b1, mitochondrial mass, and antioxidative defense enzymes, and finally failing mitochondrial fission\/fusion dynamics and deteriorating myocardial contractility as the mechanism of heart failure. The approach provides a model with induced cardiac-restricted mtDNA damage for investigation of mtDNA-based heart disease. <\/jats:p>","DOI":"10.1152\/ajpheart.00253.2014","type":"journal-article","created":{"date-parts":[[2015,6,9]],"date-time":"2015-06-09T12:10:59Z","timestamp":1433851859000},"page":"H434-H449","source":"Crossref","is-referenced-by-count":45,"title":["Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure"],"prefix":"10.1152","volume":"309","author":[{"given":"Knut H.","family":"Lauritzen","sequence":"first","affiliation":[{"name":"Department of Oral Biology, Brain and Muscle Energy Group, University of Oslo, Oslo, Norway;"},{"name":"Department of Anatomy, Institute of Basic Medical Sciences, and Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liv","family":"Kleppa","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Brain and Muscle Energy Group, University of Oslo, Oslo, Norway;"},{"name":"Department of Anatomy, Institute of Basic Medical Sciences, and Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan Magnus","family":"Aronsen","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital Ullev\u00e5l and University of Oslo, Oslo, Norway;"},{"name":"KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Norway, Oslo, Norway;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Eide","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, University of Oslo, Oslo, Norway;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harald","family":"Carlsen","sequence":"additional","affiliation":[{"name":"Department of Nutrition Research, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00d8yvind P.","family":"Haugen","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Brain and Muscle Energy Group, University of Oslo, Oslo, Norway;"},{"name":"Department of Anatomy, Institute of Basic Medical Sciences, and Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivar","family":"Sjaastad","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital Ullev\u00e5l and University of Oslo, Oslo, Norway;"},{"name":"KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Norway, Oslo, Norway;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arne","family":"Klungland","sequence":"additional","affiliation":[{"name":"Department of Nutrition Research, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway;"},{"name":"Institute of Medical Microbiology, Oslo University Hospital, Oslo, Norway;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lene Juel","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark;"},{"name":"Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H\u00e5vard","family":"Attramadal","sequence":"additional","affiliation":[{"name":"Institute for Surgical Research, Oslo University Hospital, Oslo, Norway; and"},{"name":"Center for Heart Failure Research, University of Oslo, Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon","family":"Storm-Mathisen","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Institute of Basic Medical Sciences, and Healthy Brain Ageing Centre, University of Oslo, Oslo, Norway;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda H.","family":"Bergersen","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, Brain and Muscle Energy Group, University of Oslo, Oslo, Norway;"},{"name":"Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.849919"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/23.17.3605"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/0471142905.hg1903s63"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehs275"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.08.1021"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.525"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.21.4953"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr294"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200211046"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.026"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.112.003012"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2012.03.008"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.17.9997"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.12.5547"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.33.22968"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.143.2.359"},{"key":"B17","first-page":"291","volume":"148","author":"Hill MF","year":"1996","journal-title":"Am J Pathol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.96.7.2414"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.02.023"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3308"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.88.5.529"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1101\/gad.6.3.380"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1996.tb00710.x"},{"key":"B24","first-page":"1161","volume":"85","author":"King M","year":"2012","journal-title":"Am Fam Physician"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2014.07.001"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2011.04.011"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2011.02.006"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01149-09"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700523"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/ng1295-376"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5446.1897"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvp092"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2009.2940"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.97.16.1536"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302562"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00936.2012"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/BF00220763"},{"key":"B38","first-page":"385","volume":"40","author":"Meyers DE","year":"2013","journal-title":"Tex Heart Inst J"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/gene.20175"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.004042"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/25.4.750"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2828(91)90102-R"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00310.2009"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2013.00102"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00262.2012"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fnene.2013.00007"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.09.002"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.2.119"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2007.06.035"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/21.11.2579"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0042805"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/nature02517"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00554.2011"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016601928465"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.2174\/138161282035140911142118"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00157.2011"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1126\/science.1219855"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00695-8"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00253.2014","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,15]],"date-time":"2020-05-15T09:12:15Z","timestamp":1589533935000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.00253.2014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,1]]},"references-count":58,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2015,8,1]]}},"alternative-id":["10.1152\/ajpheart.00253.2014"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00253.2014","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,1]]}}}