Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during Apoptosis

Kenichi Shimada, Timothy R. Crother, Justin Karlin, Jargalsaikhan Dagvadorj, Norika Chiba, Shuang Chen, V. Krishnan Ramanujan, Andrea J. Wolf, Laurent Vergnes, David M. Ojcius, Altan Rentsendorj, Mario Vargas, Candace Guerrero, Yinsheng Wang, Katherine A. Fitzgerald, David M. Underhill, Terrence Town, Moshe Arditi

Research output: Contribution to journalArticlepeer-review

1515 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)401-414
Number of pages14
Issue number3
StatePublished - Mar 23 2012

Bibliographical note

Funding Information:
We thank P. Sun, W. Zhang, and G. Huang for expert technical assistance. We are grateful to G. Nuñez (University of Michigan) for kindly providing the pSFFV-neo plasmid, to R.A. Flavell (Yale University) for supplying Casp1 –/– mice, and to E. Latz (University of Bonn) for kindly providing the NLRP3 plasmid. This work was supported by National Institutes of Health (NIH) grants HL-66436 and AI-067995 (to M.A.). T.T. is supported by NIH grants AG-029726 and NS-076794 and is the inaugural holder of the Ben Winters Endowed Chair in Regenerative Medicine at CSMC. D.M. Underhill is supported by NIH grant GM-085796 and holds the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease at CSMC.


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