Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure (original) (raw)
- Letter
- Published: 25 April 2012
- Shungo Hikoso1,
- Osamu Yamaguchi1,
- Manabu Taneike1,2,
- Toshihiro Takeda1,
- Takahito Tamai1,
- Jota Oyabu1,
- Tomokazu Murakawa1,
- Hiroyuki Nakayama3,
- Kazuhiko Nishida1,2,
- Shizuo Akira4,5,
- Akitsugu Yamamoto6,
- Issei Komuro1 &
- …
- Kinya Otsu1,2
Nature volume 485, pages 251–255 (2012)Cite this article
- 22k Accesses
- 895 Citations
- 67 Altmetric
- Metrics details
Subjects
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Mann, D. L. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ. Res. 91, 988–998 (2002)
Article CAS Google Scholar - Pollack, Y., Kasir, J., Shemer, R., Metzger, S. & Szyf, M. Methylation pattern of mouse mitochondrial DNA. Nucleic Acids Res. 12, 4811–4824 (1984)
Article CAS Google Scholar - Cardon, L., Burge, C., Clayton, D. A. & Karlin, S. Pervasive CpG suppression in animal mitochondrial genomes. Proc. Natl Acad. Sci. USA 91, 3799–3803 (1994)
Article ADS CAS Google Scholar - Gray, M. W., Burger, G. & Lang, B. F. Mitochondrial evolution. Science 283, 1476–1481 (1999)
Article ADS CAS Google Scholar - Nakai, A. et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nature Med. 13, 619–624 (2007)
Article CAS Google Scholar - Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000)
Article ADS CAS Google Scholar - Taanman, J.-W. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta Bioenerget. 1410, 103–123 (1999)
Article CAS Google Scholar - Collins, L., Hajizadeh, S., Holme, E., Jonsso, I. & Tarkowski, A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 75, 995–1000 (2004)
Article CAS Google Scholar - Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008)
Article ADS CAS Google Scholar - Meerson, F., Zaletayeva, T., Lagutchev, S. & Pshennikova, M. Structure and mass of mitochondria in the process of compensatory hyperfunction and hypertrophy of the heart. Exp. Cell Res. 36, 568–578 (1964)
Article CAS Google Scholar - Bugger, H. et al. Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovasc. Res. 85, 376–384 (2010)
Article ADS CAS Google Scholar - Evans, C. J. & Aguilera, R. J. DNase II: genes, enzymes and function. Gene 322, 1–15 (2003)
Article CAS Google Scholar - Kawane, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998–1002 (2006)
Article ADS CAS Google Scholar - Ashley, N., Harris, D. & Poulton, J. Detection of mitochondrial DNA depletion in living human cells using PicoGreen staining. Exp. Cell Res. 303, 432–446 (2005)
Article CAS Google Scholar - Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000)
Article CAS Google Scholar - Yamaguchi, O. et al. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J. Clin. Invest. 114, 937–943 (2004)
Article CAS Google Scholar - Lentz, S. I. et al. Mitochondrial DNA (mtDNA) biogenesis: visualization and duel incorporation of BrdU and EdU into newly synthesized mtDNA in vitro. J. Histochem. Cytochem. 58, 207–218 (2010)
Article CAS Google Scholar - Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010)
Article CAS Google Scholar - Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010)
Article ADS CAS Google Scholar - Stunz, L. et al. Inhibitory oligonucleotides specifically block effects of stimulatory CpG oligonucleotides in B cells. Eur. J. Immunol. 32, 1212–1222 (2002)
Article CAS Google Scholar - Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81, 1–5 (2007)
Article CAS Google Scholar - Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature Immunol. 12, 222–230 (2011)
Article CAS Google Scholar - Yamaguchi, O. et al. Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling. Proc. Natl Acad. Sci. USA 100, 15883–15888 (2003)
Article ADS CAS Google Scholar - Koizumi, T. Deoxyribonuclease II (DNase II) activity in mouse tissues and body fluids. Exp. Anim. 44, 169–171 (1995)
Article CAS Google Scholar - Lu, Z. et al. Participation of autophagy in the degeneration process of rat hepatocytes after transplantation following prolonged cold preservation. Arch. Histol. Cytol. 68, 71–80 (2005)
Article Google Scholar - Mosgoller, W. et al. Distribution of DNA in human Sertoli cell nucleoli. J. Histochem. Cytochem. 41, 1487–1493 (1993)
Article CAS Google Scholar
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).
Author information
Authors and Affiliations
- 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 - Cardiovascular Division, King’s College London, London SE5 9NU, UK,
Manabu Taneike, Kazuhiko Nishida & Kinya Otsu - Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, 565-0871, Osaka, Japan
Hiroyuki Nakayama - Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, 565-0871, Osaka, Japan
Shizuo Akira - Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871, Osaka, Japan
Shizuo Akira - Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, 526-0829, Shiga, Japan
Akitsugu Yamamoto
Authors
- Takafumi Oka
You can also search for this author inPubMed Google Scholar - Shungo Hikoso
You can also search for this author inPubMed Google Scholar - Osamu Yamaguchi
You can also search for this author inPubMed Google Scholar - Manabu Taneike
You can also search for this author inPubMed Google Scholar - Toshihiro Takeda
You can also search for this author inPubMed Google Scholar - Takahito Tamai
You can also search for this author inPubMed Google Scholar - Jota Oyabu
You can also search for this author inPubMed Google Scholar - Tomokazu Murakawa
You can also search for this author inPubMed Google Scholar - Hiroyuki Nakayama
You can also search for this author inPubMed Google Scholar - Kazuhiko Nishida
You can also search for this author inPubMed Google Scholar - Shizuo Akira
You can also search for this author inPubMed Google Scholar - Akitsugu Yamamoto
You can also search for this author inPubMed Google Scholar - Issei Komuro
You can also search for this author inPubMed Google Scholar - Kinya Otsu
You can also search for this author inPubMed Google Scholar
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.
Corresponding author
Correspondence toKinya Otsu.
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
PowerPoint slides
Rights and permissions
About this article
Cite this article
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
- Received: 26 June 2011
- Accepted: 01 March 2012
- Published: 25 April 2012
- Issue Date: 10 May 2012
- DOI: https://doi.org/10.1038/nature10992
Editorial Summary
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.