Mitochondrial DNA That Escapes from Autophagy Causes Inflammation and Heart Failure

By T. Oka, S. Hikoso, O. Yamaguchi, Manabu Taneike, Toshihiro Takeda, Takahito Tamai, Jota Oyabu, Tomokazu Murakawa, H. Nakayama, K. Nishida and 4 more. Nature, 2012

1,178 citations recorded by the source corpus.

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. 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.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3f95d8f0afcda33eb8002d1afa1e159ff6dabd34

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Citations in the corpus

A new pathway for mitochondrial quality control: mitochondrial‐derived vesicles (2014, background): “This pathway was shown to become activated within the endosome of cells lacking the lysosomal DNAseII (Oka et al, 2012).”
The Mitochondrial Basis of Aging (2016, background): “The importance of this mitochondrial-elicited TLR9 response can be seen in a number of important medical inflammatory states, including trauma (Zhang et al., 2010) and heart failure (Oka et al., 2012). mtDNA can also activate the NLRP3 inflammasome (Nakahira et al., 2011; Shimada et al., 2012).”
Cardiac Metabolism in Heart Failure - Implications beyond ATP production (2013, neutral): “Similarly, AMPK plays an important role in the regulation of autophagy, which has been implicated in ventricular hypertrophy(116) and inflammation.(121) Given that ventricular remodeling may occur early in the development of HF, studies examining the impact of early AMPK activation on pathological r”
Transcellular degradation of axonal mitochondria (2014, background): “It is noteworthy that mtDNA is highly immunogenic (14); for example, mtDNA that is not properly degraded by autophagy can be released and cause cardiomyopathy (15).”
Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. (2013, background): “…cardiolipin, and various other mitochondrial breakdown products, known as damage-associated molecular patterns (DAMPs), which can elicit an inflammatory re- Cite this article as Cold Spring Harb Perspect Biol 2013;5:a021220 9 sponse (Zhang et al. 2010a,b; Krysko et al. 2011; Oka et al. 2012).”
Mitochondrial DNA in inflammation and immunity (2020, positive): “Delving deeper into the mechanism, the authors found that this was due to an increase in mtDNA which has escaped degradation, thus activating a TLR9-dependent inflammatory response [171].”
STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors (2014, background): “I DNA (Oka et al., 2012) or through released exosomes.”