Letter | Published:

Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure

Nature volume 485, pages 251255 (10 May 2012) | Download Citation

  • A Corrigendum to this article was published on 19 September 2012


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 failure1. 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 DNA2,3,4. Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes5. 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 DNA6, 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.

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We thank S. Nagata and K. Kawane, Kyoto University, for discussions and a gift of Dnase2aflox/flox mice, and Y. Uchiyama, Juntendo University, for anti-LC3 antibody. We also thank K. Takada for technical assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan and research grants from Mitsubishi Pharma Research Foundation and the British Heart Foundation (CH/11/3/29051, RG/11/12/29052).

Author information


  1. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

    • Takafumi Oka
    • , Shungo Hikoso
    • , Osamu Yamaguchi
    • , Manabu Taneike
    • , Toshihiro Takeda
    • , Takahito Tamai
    • , Jota Oyabu
    • , Tomokazu Murakawa
    • , Kazuhiko Nishida
    • , Issei Komuro
    •  & Kinya Otsu
  2. Cardiovascular Division, King’s College London, London SE5 9NU, UK

    • Manabu Taneike
    • , Kazuhiko Nishida
    •  & Kinya Otsu
  3. Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan

    • Hiroyuki Nakayama
  4. Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan

    • Shizuo Akira
  5. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan

    • Shizuo Akira
  6. Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan

    • Akitsugu Yamamoto


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S.A. and I.K. provided intellectual input; K.O. was responsible for the overall study design and writing the manuscript. The other authors performed experiments and analysed data. All authors contributed to the discussions.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kinya Otsu.

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