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. 2012 May 10;485(7397):251-5.
doi: 10.1038/nature10992.

Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure

Takafumi Oka  1 , 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
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"V体育ios版" Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure

Takafumi Oka et al. Nature. .

"V体育2025版" Erratum in

  • Nature. 2012 Oct 11;490(7419):292

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 failure. 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. Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes VSports手机版. 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, 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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Figures

Fig. 1
Fig. 1. TAC-induced cardiomyopathy in Dnase2a−/−mice
a, Survival ratio after TAC (n = 7 – 14/group). b – g, 10 days after TAC. b, Gross appearance of hearts. Scale bar, 2 mm. c, Echocardiography. Scale bars, 0.2 sec and 5 mm. Echocardiographic (d) and physiological (e) parameters (n = 7 – 13/group). LVIDd and LVIDs indicate end-diastolic and end-systolic left ventricle (LV) internal dimension, respectively; LVFS, LV fractional shortening; HW/BW, heart/body weight. Hematoxylin-eosin-stained (f) and Azan-Mallory-stained (g) heart sections. Scale bar, 100 μm. Data are mean ± s.e.m. *P < 0.05 versus all other groups, †P < 0.05 versus sham-operated controls.
Fig. 2
Fig. 2. Pressure overload-induced inflammatory responses in Dnase2a−/− mice 2 days after TAC
Mice are analyzed 2 days after TAC (a – c). a, Hematoxylin-eosin-stained heart sections. Scale bar, 100 μm. b, Azan-Mallory-stained sections. Scale bar, 100 μm. c, Immunohistochemical analysis using antibodies to CD45, CD68, Ly6G and CD3. Scale bar, 100 μm.
Fig. 3
Fig. 3. Deposition of mitochondrial DNA in autolysosomes in pressure-overloaded Dnase2a−/− hearts
Mice were analyzed 2 days after TAC (a, e). a, Electron microscopic analysis. Images of mitochondria at higher magnification are shown in subsets. Scale bar, 1 μm. b, Autolysosome after incubation with anti-DNA antibody and 10 nm gold staining. Scale bar, 200 nm. Arrows indicate labeled DNA. Double staining of heart sections with EdU (green) and anti-LAMP2a antibody (red) (c), EdU (green) and anti-LC3 antibody (red) (d) or EdU and anti-TLR9 antibody (red) (e). Arrows indicate EdU-positive and LAMP2a-, LC3- or TLR9-positive structures. Scale bar, 10 μm.
Fig. 4
Fig. 4. Inhibition of TLR9 attenuated TAC-induced heart failure
a, Survival ratio of TAC-operated ODN-treated mice (n = 6 – 10/group). b - d, 4 days after TAC. b, Echocardiography. Scale bars, 0.2 sec and 5 mm. c, Echocardiographic parameters. Open and closed bars represent ODN2088 control- and ODN2088-treated groups, respectively (n = 5 – 8/group). d, Immunohistochemical analysis. Scale bar, 100 μm. TLR9-deficient mice were analyzed 10 weeks after TAC (e, f). e, Scale bars, 0.2 sec and 5 mm. f, Echocardiographic parameters (n = 6 – 10/group). Data are mean ± s.e.m. *P < 0.05 versus all other groups.
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References

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