Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure

Takafumi Oka, Shungo Hikoso, Osamu Yamaguchi, Manabu Taneike, Toshihiro Takeda, Takahito Tamai, Jota Oyabu, Tomokazu Murakawa, Hiroyuki Nakayama, Kazuhiko Nishida, Shizuo Akira, Akitsugu Yamamoto, Issei Komuro, Kinya Otsu

Research output: Contribution to journalArticlepeer-review

912 Citations (Scopus)


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(2-4). Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome systemin 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-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.

Original languageEnglish
Pages (from-to)251-255
Number of pages6
Issue number7397
Publication statusPublished - 10 May 2012


Dive into the research topics of 'Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure'. Together they form a unique fingerprint.

Cite this