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Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure
Open accessAbstract
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.
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“Mitochondria are a source of damage-associated molecular patterns (DAMPs), and among others, mtDNA has been shown to induce a pro-inflammatory state (Zhang et al, 2010;Oka et al, 2012;Wenceslau et al, 2014).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Oka et al, 2012
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In the citing paper
“APS patients met the 2006 revised Sapporo Criteria (3)”
From Identification of Mitofusin 1 and Complement Component 1q Subcomponent Binding Protein as Mitochondrial Targets in Systemic Lupus Erythematosus (2022) · cites this paper as [3]
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In the citing paper
“Extracellular mitochondria have been identified in damaged tissues (8, 18–20); diverse inflammatory conditions (11, 12, 14, 21–24); and in the blood of critical care patients (22).”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [20]
Experimental — accuracy not yet measuredIn the citing paper
“MtDNA has been reported to activate immunity through two distinct pathways, namely Toll-like receptor 9 (TLR9; Zhang et al, 2010;Oka et al, 2012;Liu et al, 2015), and cGAS activation (White et al, 2014;West et al, 2015).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Oka et al, 2012
In the citing paper
“Recent data have established a relationship between autophagy malfunction and presence of undegraded mtDNA, which is recognized by TLR9 and results in inflammation (Nakahira et al, 2011;Oka et al, 2012).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Oka et al, 2012
In the citing paper
“Based on data indicating that autophagy malfunction caused mtDNA-mediated inflammation (Nakahira et al, 2011;Oka et al, 2012)”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as Oka et al, 2012
In the citing paper
“| Cardiomyopathies | Cardiomyocyte‐specific deletion of Dnase2a | Left ventricular dilatation, severe contractile dysfunction, inflammation and premature death from sustained PO, linked to mitochondrial misalignment and aggregation | Oka et al (2012) |”
From Autophagy in major human diseases (2021) · cites this paper as Oka et al (2012)
In the citing paper
“Accumulating evidence suggests that mitophagy impairment can induce cardiomyocyte death and HF [206,207,208,209].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [209]
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Self-citation
Metadata
- Authors
- Oka, T., Hikoso, S., Yamaguchi, O., Taneike, M., Takeda, T., Tamai, T., Oyabu, J., Murakawa, T., Nakayama, H., Nishida, K., Akira, S., Yamamoto, A., Komuro, I., & Otsu, K.
- Affiliations
- The University of Osaka (JP)
- King's College London (GB)
- Immunology Frontier Research Center, The University of Osaka (JP)
- Nagahama Institute of Bio-Science and Technology (JP)
- Corresponding author
- Otsu, Kinya
- ORCID
- Venue
- Nature
- Published
- 2012-04-25
- Volume
- 485
- Issue
- 7397
- Pages
- 251-255
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3378041
- OpenAlex
- W2092943609
- Cited by
- 1,201
- References
- 30
- Citations by year
- 2026: 75 · 2025: 71 · 2024: 85 · 2023: 80 · 2022: 98 · 2021: 97 · 2020: 85 · 2019: 79 · 2018: 77 · 2017: 107 · 2016: 75 · 2015: 83 · 2014: 80 · 2013: 74 · 2012: 34
- FWCI
- 64.37
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-09-19)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- British Heart Foundation (CH/11/3/29051, RG/11/12/29052)
- Japan Society for the Promotion of Science (21390240, 21229010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- mitochondrial DNA, autophagy, heart failure, inflammation, TLR9, cardiomyocytes, DNase II, myocarditis, dilated cardiomyopathy, pressure overload, autolysosomes, oligodeoxynucleotides, cardiac dysfunction
- MeSH terms
- Alleles, Animals, Aorta, Autophagy, Constriction, Pathologic, DNA, Mitochondrial, Endodeoxyribonucleases, Heart, Cardiomegaly, Heart Failure, Lysosomes, Male, Mitochondria, Myocarditis, Myocardium, Pressure, RNA, Messenger, Signal Transduction, Cytokines, Myocytes, Cardiac, Toll-Like Receptor 9, Mice
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