title: Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure.
abstract: Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure. However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA. Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes. Here we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts showed infiltration of inflammatory cells and increased messenger RNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA, or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9 ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Oka
authors.forename: Shungo
authors.initials: S
authors.lastname: Hikoso
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Taneike
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takeda
authors.forename: Takahito
authors.initials: T
authors.lastname: Tamai
authors.forename: Jota
authors.initials: J
authors.lastname: Oyabu
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Murakawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishida
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Akitsugu
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Kinya
authors.initials: K
authors.lastname: Otsu
mesh_terms: D000483:Alleles; D000818:Animals; D001011:Aorta / Q000473:pathology; D001343:Autophagy; D006332:Cardiomegaly / Q000209:etiology; D003251:Constriction, Pathologic / Q000150:complications; D016207:Cytokines / Q000235:genetics; D004272:DNA, Mitochondrial / Q000276:immunology* / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria; D009205:Myocarditis / Q000209:etiology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011312:Pressure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D051217:Toll-Like Receptor 9; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II