Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure

 Takafumi Oka et al., Nature. 485:251-255 (2012)

Speaker: Yu-Chi Su (蘇育琦)                                        Time: 15:10~16:00, Feb. 27, 2013

Commentator: Dr. Ching-Ho Hsieh (謝清河 醫師)    Place: Room 601

Heart failure is a common, costly, disabling, and potentially deadly condition in developed countries. The pathogenesis of heart failure has been linked to heart inflammation. However, the mechanisms leading to initiate inflammatory responses are still unknown. Mitochondria DNA is similar to bacteria DNA that is evolutionary endosymbionts and contains unmethylated CpG motifs. The damaged of mitochondria caused by external haemodynamic stress, example for thoracic transverse aortic constriction (TAC), can be removed via autophagy process in cardiomyocytes. DNase II is an acid DNase found in lysosome and is essential for degrading DNA of apoptotic cells after macrophages engulf them. In this study, the authors tried to identify the role of DNase II in autophagy systems which protect haemodynamic stress-induced heart inflammation. The authors used TAC to induce cardiac hypertrophy in early time and following with heart failure in mice. Up-regulated DNase II activity was found in hypertrophy hearts, but not in failing hearts, which contained accumulated mitochondria DNA in autolysosomes. In order to clarify the role of DNase II in autophagysystem in damaged-cardiomyocytes, the authors generated the cardiac-specific conditional knockout mice of Dnase2a (Dnase2a^-/- mice). Early in the cardiac hypertrophy stage, Dnase2a^-/- mice showed infiltration of immune cells, increased mRNA level of inflammatory cytokines. TLR9 is known to sense unmethylated DNA from bacteria or virus and localizes in endolysosomes. The authors administrated TLR9 inhibitor or ablated Tlr9 expression in Dnase2a^-/- mice after inducing TAC. They found attenuation of cardiomyopathy development and inflammation. In conclusion, the authors demonstrated that mitochondrial DNA that escapes from autophagy-mediated degradation leads to TLR9-mediated inflammatory responses in cardiomyocytes. This mechanism might imply the possibility of mitochondrial DNA inducing inflammation in chronic non-infectious inflammatory diseases.

References:

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