{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:06:05Z","timestamp":1790683565484,"version":"4.1.0"},"reference-count":23,"publisher":"National Academy of Sciences","issue":"7","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2000,3,28]]},"abstract":"<jats:p>\n                    We recently described a mouse model that reproduces important pathophysiological features of mitochondrial DNA (mtDNA) mutation diseases. The gene for mouse mitochondrial transcription factor A,\n                    <jats:italic>Tfam<\/jats:italic>\n                    (also called mtTFA), a nucleus-encoded key regulator of mtDNA expression, was targeted with\n                    <jats:italic>loxP<\/jats:italic>\n                    sites (\n                    <jats:italic>Tfam<\/jats:italic>\n                    <jats:sup>loxP<\/jats:sup>\n                    ) and disrupted\n                    <jats:italic>in vivo<\/jats:italic>\n                    by transgenic expression of\n                    <jats:italic>cre<\/jats:italic>\n                    -recombinase from the muscle creatinine kinase (\n                    <jats:italic>Ckmm<\/jats:italic>\n                    ) promoter. This promoter is active from embryonic day 13, and the knockouts had normal respiratory chain function in the heart at birth and developed mitochondrial cardiomyopathy postnatally. In this paper, we describe a heart-knockout strain obtained by mating\n                    <jats:italic>Tfam<\/jats:italic>\n                    <jats:sup>loxP<\/jats:sup>\n                    mice to animals expressing\n                    <jats:italic>cre<\/jats:italic>\n                    -recombinase from the \u03b1-myosin heavy chain (\n                    <jats:italic>Myhca<\/jats:italic>\n                    ) promoter. This promoter is active from embryonic day 8, and the knockouts had onset of mitochondrial cardiomyopathy during embryogenesis. The age of onset of cardiac respiratory chain dysfunction can thus be controlled by temporal regulation of\n                    <jats:italic>cre<\/jats:italic>\n                    -recombinase expression. Further characterization demonstrated that \u224875% of the knockouts died in the neonatal period, whereas, surprisingly, \u224825% survived for several months before dying from dilated cardiomyopathy with atrioventricular heart conduction blocks. Modifying gene(s) affect the life span of the knockouts, because \u224895% of the knockout offspring from an intercross of the longer-living knockouts survived the neonatal period. Thus, the tissue-specific knockouts we describe here not only reproduce important pathophysiological features of mitochondrial cardiomyopathy but also provide a powerful system by which to identify modifying genes of potential therapeutic value.\n                  <\/jats:p>","DOI":"10.1073\/pnas.97.7.3467","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:38:21Z","timestamp":1027679901000},"page":"3467-3472","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":159,"title":["Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy"],"prefix":"10.1073","volume":"97","author":[{"given":"Hong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, CMM L8:02, and Department of Women and Children's Health, Karolinska Hospital, S-17176 Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524; and Unit\u00e9 de Recherches sur les Handicaps G\u00e9n\u00e9tiques de l'Enfant (Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U393), H\u00f4spital des Enfants..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, CMM L8:02, and Department of Women and Children's Health, Karolinska Hospital, S-17176 Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524; and Unit\u00e9 de Recherches sur les Handicaps G\u00e9n\u00e9tiques de l'Enfant (Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U393), H\u00f4spital des Enfants..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Wilhelmsson","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, CMM L8:02, and Department of Women and Children's Health, Karolinska Hospital, S-17176 Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524; and Unit\u00e9 de Recherches sur les Handicaps G\u00e9n\u00e9tiques de l'Enfant (Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U393), H\u00f4spital des Enfants..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Hansson","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, CMM L8:02, and Department of Women and Children's Health, Karolinska Hospital, S-17176 Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524; and Unit\u00e9 de Recherches sur les Handicaps G\u00e9n\u00e9tiques de l'Enfant (Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U393), H\u00f4spital des Enfants..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Thor\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, CMM L8:02, and Department of Women and Children's Health, Karolinska Hospital, S-17176 Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524; and Unit\u00e9 de Recherches sur les Handicaps G\u00e9n\u00e9tiques de l'Enfant (Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U393), H\u00f4spital des Enfants..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Duffy","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, CMM L8:02, and Department of Women and Children's Health, Karolinska Hospital, S-17176 Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524; and Unit\u00e9 de Recherches sur les Handicaps G\u00e9n\u00e9tiques de l'Enfant (Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U393), H\u00f4spital des Enfants..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Rustin","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, CMM L8:02, and Department of Women and Children's Health, Karolinska Hospital, S-17176 Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524; and Unit\u00e9 de Recherches sur les Handicaps G\u00e9n\u00e9tiques de l'Enfant (Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U393), H\u00f4spital des Enfants..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils-G\u00f6ran","family":"Larsson","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, CMM L8:02, and Department of Women and Children's Health, Karolinska Hospital, S-17176 Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden; Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524; and Unit\u00e9 de Recherches sur les Handicaps G\u00e9n\u00e9tiques de l'Enfant (Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U393), H\u00f4spital des Enfants..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2000,3,28]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ge.29.120195.001055"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5407.1482"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2796.1999.00514.x"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(99)00854-6"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00763100"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02002711"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(97)01266-3"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.23.10614"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0960-8966(93)90040-Q"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.6.1117"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0398-231"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/5089"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)31568-0"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(94)90055-8"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1977.1"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.111.6.2427"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.78.3.504"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.25.4.473"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(80)90224-0"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7618084"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0997-88"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/9635"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.113.3.1017"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.97.7.3467","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T17:23:14Z","timestamp":1649870594000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.97.7.3467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,3,28]]},"references-count":23,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2000,3,28]]}},"alternative-id":["10.1073\/pnas.97.7.3467"],"URL":"https:\/\/doi.org\/10.1073\/pnas.97.7.3467","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,3,28]]},"assertion":[{"value":"1999-11-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-01-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2000-03-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}