Journal
IMMUNITY
Volume 55, Issue 8, Pages 1370-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2022.06.007
Keywords
-
Categories
Funding
- NCI Cancer Center Support Grant (CCSG) [P30CA23100]
- NIAMS [K01AR077111]
- NIH [R37 AI043477, U54 CA260591, DK100640, AR069876]
Ask authors/readers for more resources
In stressed mitochondria, oxidized mtDNA fragments are released and trigger inflammation. Understanding this process is important for the development of treatments for chronic inflammatory diseases.
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-1b (IL-1b) production and mtDNA release in mice.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available