title: Twinkle overexpression prevents cardiac rupture after myocardial infarction by alleviating impaired mitochondrial biogenesis.
abstract: Cardiac rupture is a fatal complication after myocardial infarction (MI). However, the detailed mechanism underlying cardiac rupture after MI remains to be fully elucidated. In this study, we investigated the role of mitochondrial DNA (mtDNA) and mitochondria in the pathophysiology of cardiac rupture by analyzing Twinkle helicase overexpression mice (TW mice). Twinkle overexpression increased mtDNA copy number approximately twofold and ameliorated ischemic cardiomyopathy at day 28 after MI. Notably, Twinkle overexpression markedly prevented cardiac rupture and improved post-MI survival, accompanied by the suppression of MMP-2 and MMP-9 in the MI border area at day 5 after MI when cardiac rupture frequently occurs. Additionally, these cardioprotective effects of Twinkle overexpression were abolished in transgenic mice overexpressing mutant Twinkle with an in-frame duplication of amino acids 353-365, which resulted in no increases in mtDNA copy number. Furthermore, although apoptosis and oxidative stress were induced and mitochondria were damaged in the border area, these injuries were improved in TW mice. Further analysis revealed that mitochondrial biogenesis, including mtDNA copy number, transcription, and translation, was severely impaired in the border area at day 5 In contrast, Twinkle overexpression maintained mtDNA copy number and restored the impaired transcription and translation of mtDNA in the border area. These results demonstrated that Twinkle overexpression alleviated impaired mitochondrial biogenesis in the border area through maintained mtDNA copy number and thereby prevented cardiac rupture accompanied by the reduction of apoptosis and oxidative stress, and suppression of MMP activity.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and.
authors.forename: Masataka
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and tomomi_i@cardiol.med.kyushu-u.ac.jp.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and.
authors.forename: Takeo
authors.initials: T
authors.lastname: Fujino
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Arai
authors.affiliation: Department of Therapeutic Regulation of Cardiovascular Homeostasis, Center for Disruptive Cardiovascular Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Saku
authors.affiliation: Department of Therapeutic Regulation of Cardiovascular Homeostasis, Center for Disruptive Cardiovascular Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D003331:Coronary Vessels / Q000601:surgery; D004265:DNA Helicases / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004452:Echocardiography; D006341:Heart Rupture / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008026:Ligation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D001678:Organelle Biogenesis; D018384:Oxidative Stress; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D000255:Adenosine Triphosphate; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C513299:Twnk protein, mouse; D004265:DNA Helicases
keywords: Twinkle; cardiac rupture; mitochondrial biogenesis; mtDNA; oxidative stress