{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T03:28:42Z","timestamp":1794281322462,"version":"4.9.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2018,1,5]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of\n              <jats:italic>Tfam<\/jats:italic>\n              (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              <jats:italic>Tfam<\/jats:italic>\n              inactivation by Nkx2.5\n              <jats:sup>Cre<\/jats:sup>\n              caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia.\n              <jats:italic>Tfam<\/jats:italic>\n              inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic\n              <jats:italic>Tfam<\/jats:italic>\n              inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal\n              <jats:italic>Tfam<\/jats:italic>\n              inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal\n              <jats:italic>Tfam<\/jats:italic>\n              inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of\n              <jats:italic>Tfam<\/jats:italic>\n              inactivation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Mitochondrial dysfunction caused by\n              <jats:italic>Tfam<\/jats:italic>\n              inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.117.311349","type":"journal-article","created":{"date-parts":[[2017,10,12]],"date-time":"2017-10-12T00:11:00Z","timestamp":1507767060000},"page":"74-87","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":124,"title":["Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation"],"prefix":"10.1161","volume":"122","author":[{"given":"Donghui","family":"Zhang","sequence":"first","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Li","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Heims-Waldron","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassilios","family":"Bezzerides","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Guatimosim","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Guo","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Gu","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingzhu","family":"Zhou","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqiang","family":"Lin","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Ma","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Liu","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da-Zhi","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"Pu","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Boston Children\u2019s Hospital, MA (D.Z., Y.L., D.H.-W., V.B., S.G., Y.G., F.G., P.Z., Z.L., Q.M., J.L., D.-Z.W., W.T.P.); Hubei Collaborative Innovation Center for Green Transformation of Bio-Resources, Hubei Key Laboratory of Industrial Biotechnology, College of Life Sciences, Hubei University, Wuhan, China (D.Z.); Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital,..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1012478"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3545"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.08.008"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1661708"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.07.002"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1113987109"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2006.11.017"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.10.016"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3467"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/5089"},{"key":"e_1_3_4_12_2","first-page":"431","article-title":"Efficient Cre-mediated deletion in cardiac progenitor cells conferred by a 3\u2019UTR-ires-Cre allele of the homeobox gene Nkx2-5.","volume":"46","author":"Stanley EG","year":"2002","unstructured":"Stanley EG, Biben C, Elefanty A, Barnett L, Koentgen F, Robb L, Harvey RP. 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