Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure

• Published in: Nature (London) 2012-05, Vol.485 (7397), p.251-255
• Main Authors: Oka, Takafumi, Hikoso, Shungo, Yamaguchi, Osamu, Taneike, Manabu, Takeda, Toshihiro, Tamai, Takahito, Oyabu, Jota, Murakawa, Tomokazu, Nakayama, Hiroyuki, Nishida, Kazuhiko, Akira, Shizuo, Yamamoto, Akitsugu, Komuro, Issei, Otsu, Kinya
• Format: Article
• Language: English
• Subjects: 631/250/256; 631/80/39; 692/699/75/74; Alleles; Animals; Aorta - pathology; Autophagy; Autophagy (Cytology); Biological and medical sciences; Cardiology. Vascular system; Cardiomegaly - etiology; Cardiomyocytes; Constriction, Pathologic - complications; Cytokines; Cytokines - genetics; Development and progression; DNA, Mitochondrial - immunology; DNA, Mitochondrial - metabolism; Endodeoxyribonucleases - deficiency; Endodeoxyribonucleases - genetics; Endodeoxyribonucleases - metabolism; Genetic aspects; Health aspects; Heart; Heart - physiopathology; Heart failure; Heart Failure - etiology; Heart Failure - immunology; Heart Failure - metabolism; Heart Failure - pathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humanities and Social Sciences; Inflammation; letter; Lysosomes - enzymology; Lysosomes - metabolism; Male; Medical sciences; Mice; Microorganisms; Mitochondria; Mitochondrial DNA; Mortality; multidisciplinary; Myocarditis - etiology; Myocarditis - immunology; Myocarditis - metabolism; Myocarditis - pathology; Myocarditis. Cardiomyopathies; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Pathogenesis; Physiological aspects; Pressure; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Science; Science (multidisciplinary); Signal Transduction; Survival analysis; Toll-Like Receptor 9 - antagonists & inhibitors; Toll-Like Receptor 9 - deficiency; Toll-Like Receptor 9 - immunology; Toll-Like Receptor 9 - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature10992

Mitochondrial DNA escaping from the autophagy pathway can trigger inflammation through Toll-like receptor (TLR) 9, leading to abnormalities in cardiac structure and function, and increased mortality. Heart failure link to mitochondrial DNA Inflammation has been implicated in the pathogenesis of heart failure, but what initiates the inflammation has been unclear. This study identifies an inflammatory pathway that participates in the pathogenesis of heart failure in a mouse model. Mitochondria damaged by external stress are normally degraded by autophagy. The authors show that mitochondrial DNA released in this way in heart cells can trigger a Toll-like receptor (TLR) 9-mediated inflammatory response, leading to abnormalities in cardiac structure and function, and increased mortality. 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 1 . 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 2 , 3 , 4 . Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes 5 . 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 6 , 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-ty