New mitochondrial DNA synthesis enables NLRP3 inflammasome activation
Open accessAbstract
Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.
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The combination of replicating mtDNA and ROS would oxidize mtDNA, which would be released to activate the innate immune system inflammasome and Type I interferon pathway.
“The combination of replicating mtDNA and ROS would oxidize the mtDNA, which would be released to activate the innate immune system inflammasome and the Type I interferon pathway (West and Shadel, 2017; Zhong et al., 2018).”
From Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact (2020) · cites this paper as Zhong et al., 2018
The Discussion (page unavailable) links newly synthesized mtDNA, oxidation, release of ox-mtDNA fragments, and NLRP3 inflammasome activation. The paper does not show that released ox-mtDNA activates the type I interferon pathway; its discussion of IRF1 concerns an upstream regulator of mtDNA synthesis and NLRP3 activation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCytosolic mtDNA can activate the NLRP3 inflammasome.
“mtDNA has been shown to activate the NLRP3 inflammasome.”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Zhong et al., 2018
Priming of macrophages generates newly synthesized, oxidized mtDNA fragments that activate the NLRP3 inflammasome, suggesting NLRP3 preferably binds oxidized mtDNA.
“Furthermore, a more recent study also demonstrated that priming of macrophages generates newly synthesized, oxidized mtDNA fragments that activate the NLRP3 inflammasome, suggesting that NLRP3 preferably binds oxidized mtDNA (Zhong et al., 2018).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Zhong et al., 2018
CytoDNA species share similar signaling pathways, most prominently the cGAS-STING pathway, although mtDNA, MN, and other DNA damage-associated DNA fragments are thought to also activate the AIM2 and NLRP3 inflammasome pathway.
“Third, cytoDNA species share similar signaling pathways, most prominently the cGAS-STING pathway, although mtDNA, MN, and other DNA damage-associated DNA fragments are thought to also activate the AIM2 and NLRP3 inflammasome pathway (Di Micco et al., 2016; Motwani and Fitzgerald, 2017; Zhong et al., 2018).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Zhong et al., 2018
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- Authors
- Zhong, Z., Liang, S., Sanchez-Lopez, E., He, F., Shalapour, S., Lin, X.-J., Wong, J., Ding, S., Seki, E., Schnabl, B., Hevener, A. L., Greenberg, H. B., Kisseleva, T., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Jinan University (CN)
- VA Palo Alto Health Care System (US)
- Cedars-Sinai Medical Center (US)
- University of California, Los Angeles (US)
- Corresponding author
- Karin, Michael
- ORCID
- Venue
- Nature
- Published
- 2018-07-25
- Volume
- 560
- Issue
- 7717
- Pages
- 198-203
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6329306
- OpenAlex
- W2884912010
- Cited by
- 1,208
- References
- 33
- Citations by year
- 2026: 150 · 2025: 182 · 2024: 165 · 2023: 173 · 2022: 173 · 2021: 132 · 2020: 120 · 2019: 93 · 2018: 15 · 2017: 1
- FWCI
- 32.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (R01AA020172, U01AA022614)
- National Cancer Institute (R01CA163798, P01CA128814, R01CA211794)
- National Institute of Allergy and Infectious Diseases (K99AI135031, R01AI043477, R37AI043477)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK111866, R01DK109724, P30DK063491, R01DK101737, R01DK085252, R01DK099205)
- National Institute of Environmental Health Sciences (P42ES010337)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- NLRP3 inflammasome, mitochondrial DNA synthesis, CMPK2, Toll-like receptors, MyD88, TRIF, IRF1, macrophages, inflammation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Cytosol, DNA, Mitochondrial, Lipopolysaccharides, Macrophages, Mitochondria, Nucleoside-Phosphate Kinase, Oxidation-Reduction, Signal Transduction, Interferon Regulatory Factor-1, Toll-Like Receptors, Mice, Biocatalysis, Inflammasomes
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