Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure (original) (raw)

Nature volume 485, pages 251–255 (2012)Cite this article

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A Corrigendum to this article was published on 19 September 2012

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 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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Acknowledgements

We thank S. Nagata and K. Kawane, Kyoto University, for discussions and a gift of Dnase2a flox/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).

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, 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, 565-0871, Osaka, Japan
    Hiroyuki Nakayama
  4. Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, 565-0871, Osaka, Japan
    Shizuo Akira
  5. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871, Osaka, Japan
    Shizuo Akira
  6. Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, 526-0829, Shiga, Japan
    Akitsugu Yamamoto

Authors

  1. Takafumi Oka
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  2. Shungo Hikoso
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  3. Osamu Yamaguchi
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  4. Manabu Taneike
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  5. Toshihiro Takeda
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  6. Takahito Tamai
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  7. Jota Oyabu
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  8. Tomokazu Murakawa
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  9. Hiroyuki Nakayama
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  10. Kazuhiko Nishida
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  11. Shizuo Akira
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  12. Akitsugu Yamamoto
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  13. Issei Komuro
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  14. Kinya Otsu
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Contributions

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.

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Correspondence toKinya Otsu.

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The authors declare no competing financial interests.

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Oka, T., Hikoso, S., Yamaguchi, O. et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure.Nature 485, 251–255 (2012). https://doi.org/10.1038/nature10992

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Editorial Summary

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.

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