The DOI matches its Crossref record; 74 of the 74 references it cites were found in a registry or an index.
Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling
Open accessAbstract
Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.
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“Karin et al. have shown that Ca2+ overload can induce mitochondrial activation and the release of mitochondrial DNA (mtDNA) (19).”
From Matrix mechanical remodeled carrier-free nanosystem for programmable closed-loop reversal of liver fibrosis via STING alkylation (2025) · cites this paper as [19]
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Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis
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Han, H., Yu, D., Liu, Y., Jia, H., & Liu, W. (2025) · Science Advances · doi:10.1126/sciadv.adz4126 · Cited by 7
“Karin et al. have shown that Ca 2 + overload can induce mitochondrial activation and the release of mitochondrial DNA (mtDNA) ( 19 ).”
Metadata
- Authors
- Xian, H., Watari, K., Sanchez-Lopez, E., Offenberger, J., Onyuru, J., Sampath, H., Ying, W., Hoffman, H. M., Shadel, G. S., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Rutgers, The State University of New Jersey (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Karin, Michael
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 55
- Issue
- 8
- Pages
- 1370-1385.e8
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC9378606
- OpenAlex
- W4285098776
- Cited by
- 850
- References
- 74
- Citations by year
- 2026: 276 · 2025: 249 · 2024: 184 · 2023: 120 · 2022: 21
- FWCI
- 47.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- ImmPort
- Funders
- National Cancer Institute (U54CA260591, P30CA023100, P30CA014195)
- National Institute of Allergy and Infectious Diseases (R01AI043477, R37AI043477, R25AI147376)
- National Institute of Diabetes and Digestive and Kidney Diseases (K99DK100640, R00DK100640)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR077111, P30AR073761, R01AR069876)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- oxidized mitochondrial DNA, mitochondrial permeability transition pore, voltage-dependent anion channel, NLRP3 inflammasome, cGAS-STING pathway, interferon signaling, macrophages, mitochondrial calcium uptake, OGG1, FEN1, extracellular DNA, IL-1β, chronic inflammation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Mitochondrial Permeability Transition Pore, Animals, DNA, Mitochondrial, Interferons, Mitochondria, Nucleotidyltransferases, Mice, Inflammasomes
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