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

Hongxu XianLaboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USAKosuke WatariLaboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USAElsa Sánchez‐LópezLaboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA; Department of Orthopedic Surgery, School of Medicine, UCSD, La Jolla, CA 92093, USAJoseph OffenbergerLaboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USAJanset OnyuruDivision of Pediatric Allergy, Immunology, and Rheumatology, Rady Children's Hospital of San Diego, University of California, San Diego, San Diego, CA, USAHarini SampathDepartment of Nutritional Sciences and New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USAWei YingDivision of Endocrinology & Metabolism, University of California, San Diego, La Jolla, CA 92093, USAHal M. HoffmanDivision of Pediatric Allergy, Immunology, and Rheumatology, Rady Children's Hospital of San Diego, University of California, San Diego, San Diego, CA, USAGerald S. ShadelSalk Institute for Biological Studies, La Jolla, CA 92037, USAMichael KarinLaboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA. Electronic address: [email protected]

2022en

ABI

Annotatsiya

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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DOI: 10.1016/j.immuni.2022.06.007

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