2. Academic Validation
  3. Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling

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

  • Immunity. 2022 Aug 9;55(8):1370-1385.e8. doi: 10.1016/j.immuni.2022.06.007.
Hongxu Xian 1,  Kosuke Watari 1,  Elsa Sanchez-Lopez 2,  Joseph Offenberger 1,  Janset Onyuru 3,  Harini Sampath 4,  Wei Ying 5,  Hal M Hoffman 3,  Gerald S Shadel 6,  Michael Karin 7
Affiliations

Affiliations

  • 1 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA.
  • 2 Laboratory 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, USA.
  • 3 Division of Pediatric Allergy, Immunology, and Rheumatology, Rady Children's Hospital of San Diego, University of California, San Diego, San Diego, CA, USA.
  • 4 Department of Nutritional Sciences and New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA.
  • 5 Division of Endocrinology & Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
  • 6 Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • 7 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.
PMID: 35835107 DOI: 10.1016/j.immuni.2022.06.007
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.

Keywords

FEN1; NLRP3 inflammasome; OGG1; Ox-mtDNA; VDAC; cGAS-STING; mPTP; mitochondria; mtDNA.

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