Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis
Open accessAbstract
We report that in the presence of signal 1 (NF-κB), the NLRP3 inflammasome was activated by mitochondrial apoptotic signaling that licensed production of interleukin-1β (IL-1β). NLRP3 secondary signal activators such as ATP induced mitochondrial dysfunction and apoptosis, resulting in release of oxidized mitochondrial DNA (mtDNA) into the cytosol, where it bound to and activated the NLRP3 inflammasome. The antiapoptotic protein Bcl-2 inversely regulated mitochondrial dysfunction and NLRP3 inflammasome activation. Mitochondrial DNA directly induced NLRP3 inflammasome activation, because macrophages lacking mtDNA had severely attenuated IL-1β production, yet still underwent apoptosis. Both binding of oxidized mtDNA to the NLRP3 inflammasome and IL-1β secretion could be competitively inhibited by the oxidized nucleoside 8-OH-dG. Thus, our data reveal that oxidized mtDNA released during programmed cell death causes activation of the NLRP3 inflammasome. These results provide a missing link between apoptosis and inflammasome activation, via binding of cytosolic oxidized mtDNA to the NLRP3 inflammasome.
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mtDNA is recognized as foreign when outside mitochondria and can trigger inflammation.
“MtDNA is recognized as foreign when found outside of mitochondria and can trigger inflammation (Maekawa et al., 2019; Shimada et al., 2012; Zhang et al., 2010).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Shimada et al., 2012
Cytosolic 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 Shimada et al., 2012
During macrophage apoptosis, oxidized mtDNA is released into the cytosol, where it binds to and activates the NLRP3 inflammasome.
“Another study showed that during macrophage apoptosis, oxidized mtDNA is released into the cytosol, where it binds to and activates the NLRP3 inflammasome (Shimada et al., 2012).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Shimada et al., 2012
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- Authors
- Shimada, K., Crother, T. R., Karlin, J., Dagvadorj, J., Chiba, N., Chen, S., Ramanujan, V. K., Wolf, A. J., Vergnes, L., Ojcius, D. M., Rentsendorj, A., Vargas, M., Guerrero, C., Wang, Y., Fitzgerald, K. A., Underhill, D. M., Town, T., & Arditi, M.
- Affiliations
- Cedars-Sinai Medical Center (US)
- University of California, Los Angeles (US)
- University of California, Merced (US)
- University of California, Riverside (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Arditi, Moshe
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 36
- Issue
- 3
- Pages
- 401-414
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3312986
- OpenAlex
- W2018563185
- Cited by
- 2,282
- References
- 53
- Citations by year
- 2026: 246 · 2025: 208 · 2024: 184 · 2023: 193 · 2022: 202 · 2021: 231 · 2020: 177 · 2019: 147 · 2018: 134 · 2017: 132 · 2016: 114 · 2015: 91 · 2014: 84 · 2013: 101 · 2012: 34
- FWCI
- 39.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Scholarly Commons (University of the Pacific) (submittedVersion)
- Funders
- Rheinische Friedrich-Wilhelms-Universität Bonn
- National Institutes of Health
- National Institute on Aging (AG-029726, K99AG029726, R00AG029726)
- National Heart, Lung, and Blood Institute (HL66436, R01HL066436)
- National Institute of General Medical Sciences (GM-085796, R01GM085796)
- National Institute of Allergy and Infectious Diseases (AI-067995, R01AI067995, R56AI067995, R01AI083713)
- National Institute of Neurological Disorders and Stroke (NS-076794, R01NS076794)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- oxidized mitochondrial DNA, NLRP3 inflammasome, apoptosis, IL-1β, mitochondrial dysfunction, Bcl-2, macrophages, cytosolic DNA sensing, NF-κB signaling, programmed cell death
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Carrier Proteins, DNA, Mitochondrial, Macrophages, Mice, Inbred C57BL, Oxidation-Reduction, Salmonella typhimurium, Signal Transduction, Gene Expression, NF-kappa B, Apoptosis, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, Mice, Interleukin-1beta, Inflammasomes
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