Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure

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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: TAC-induced cardiomyopathy in Dnase2a –/– mice.
Figure 2: Pressure overload-induced inflammatory responses in Dnase2a –/– mice 2 days after TAC.
Figure 3: Deposition of mitochondrial DNA in autolysosomes in pressure-overloaded Dnase2a –/– hearts.
Figure 4: Inhibition of TLR9 attenuated TAC-induced heart failure.


  1. Mann, D. L. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ. Res. 91, 988–998 (2002)

    CAS  Article  Google Scholar 

  2. Pollack, Y., Kasir, J., Shemer, R., Metzger, S. & Szyf, M. Methylation pattern of mouse mitochondrial DNA. Nucleic Acids Res. 12, 4811–4824 (1984)

    CAS  Article  Google Scholar 

  3. 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)

    ADS  CAS  Article  Google Scholar 

  4. Gray, M. W., Burger, G. & Lang, B. F. Mitochondrial evolution. Science 283, 1476–1481 (1999)

    ADS  CAS  Article  Google Scholar 

  5. 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)

    CAS  Article  Google Scholar 

  6. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000)

    ADS  CAS  Article  Google Scholar 

  7. Taanman, J.-W. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta Bioenerget. 1410, 103–123 (1999)

    CAS  Article  Google Scholar 

  8. 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)

    CAS  Article  Google Scholar 

  9. Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008)

    ADS  CAS  Article  Google Scholar 

  10. 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)

    CAS  Article  Google Scholar 

  11. Bugger, H. et al. Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure. Cardiovasc. Res. 85, 376–384 (2010)

    ADS  CAS  Article  Google Scholar 

  12. Evans, C. J. & Aguilera, R. J. DNase II: genes, enzymes and function. Gene 322, 1–15 (2003)

    CAS  Article  Google Scholar 

  13. Kawane, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998–1002 (2006)

    ADS  CAS  Article  Google Scholar 

  14. 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)

    CAS  Article  Google Scholar 

  15. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000)

    CAS  Article  Google Scholar 

  16. 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)

    CAS  Article  Google Scholar 

  17. 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)

    CAS  Article  Google Scholar 

  18. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010)

    CAS  Article  Google Scholar 

  19. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010)

    ADS  CAS  Article  Google Scholar 

  20. Stunz, L. et al. Inhibitory oligonucleotides specifically block effects of stimulatory CpG oligonucleotides in B cells. Eur. J. Immunol. 32, 1212–1222 (2002)

    CAS  Article  Google Scholar 

  21. Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81, 1–5 (2007)

    CAS  Article  Google Scholar 

  22. 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)

    CAS  Article  Google Scholar 

  23. 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)

    ADS  CAS  Article  Google Scholar 

  24. Koizumi, T. Deoxyribonuclease II (DNase II) activity in mouse tissues and body fluids. Exp. Anim. 44, 169–171 (1995)

    CAS  Article  Google Scholar 

  25. 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 

  26. Mosgoller, W. et al. Distribution of DNA in human Sertoli cell nucleoli. J. Histochem. Cytochem. 41, 1487–1493 (1993)

    CAS  Article  Google Scholar 

Download references


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

Authors and Affiliations



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 to Kinya Otsu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-10 and Supplementary Tables 1-2. (PDF 13510 kb)

PowerPoint slides

Rights and permissions

Reprints 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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing