Cited by 850Inflammasome and immune disordersMitochondrial Function and PathologyImmune Response and Inflammation

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Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling

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Xian, Hongxu, Watari, Kosuke, Sanchez-Lopez, Elsa, Offenberger, Joseph, Onyuru, Janset, Sampath, Harini, Ying, Wei, Hoffman, Hal M., Shadel, Gerald S., Karin, Michael·2022·Immunity

DOI 10.1016/j.immuni.2022.06.007PMC PMC9378606

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Abstract

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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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: Xian, Hongxu
Watari, Kosuke
Onyuru, Janset
Sampath, Harini
Hoffman, Hal M.
Shadel, Gerald S.
Karin, Michael
Venue: Immunity
Publisher: Elsevier BV
Published: 2022-08
Volume: 55
Issue: 8
Pages: 1370-1385.e8
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2022.06.007
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 52 d)
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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Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling

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