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

Animals DNA, Mitochondrial / metabolism Inflammasomes / metabolism Interferons / metabolism Mice Mitochondria / metabolism Mitochondrial Permeability Transition Pore NLR Family, Pyrin Domain-Containing 3 Protein / metabolism Nucleotidyltransferases / metabolism
FEN1 NLRP3 inflammasome OGG1 Ox-mtDNA VDAC cGAS-STING mPTP mitochondria mtDNA

Journal

Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918

Informations de publication

Date de publication:
09 08 2022
Historique:
received: 24 01 2022
revised: 18 04 2022
accepted: 09 06 2022
pubmed: 15 7 2022
medline: 13 8 2022
entrez: 14 7 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.immuni.2022.06.007 PMID: 35835107 PMC: PMC9378606
pubmed: 35835107
pii: S1074-7613(22)00280-1
doi: 10.1016/j.immuni.2022.06.007
pmc: PMC9378606
mid: NIHMS1817878
pii:
doi:

Substances chimiques

DNA, Mitochondrial 0
Inflammasomes 0
Mitochondrial Permeability Transition Pore 0
NLR Family, Pyrin Domain-Containing 3 Protein 0
Nlrp3 protein, mouse 0
Interferons 9008-11-1
Nucleotidyltransferases EC 2.7.7.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1370-1385.e8

Subventions

Organisme : NCI NIH HHS
ID : U54 CA260591
Pays : United States
Organisme : NIAID NIH HHS
ID : R25 AI147376
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI043477
Pays : United States
Organisme : NIDDK NIH HHS
ID : R00 DK100640
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023100
Pays : United States
Organisme : NIAMS NIH HHS
ID : K01 AR077111
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI043477
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR069876
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR073761
Pays : United States
Organisme : NIDDK NIH HHS
ID : K99 DK100640
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2022 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests M.K. is a founder of Elgia Pharmaceuticals, a member of its scientific advisory board, and received research support from Gossamer Bio, Jansen Pharmaceuticals, and Merck. UCSD is in the process of applying for a patent covering the generation and use of novel anti-inflammatory therapy for ARDS listing H.X., E.S.-L., and M.K. as inventors.

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Auteurs

Hongxu Xian (H)

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA.

Kosuke Watari (K)

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA.

Elsa Sanchez-Lopez (E)

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.

Joseph Offenberger (J)

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA.

Janset Onyuru (J)

Division of Pediatric Allergy, Immunology, and Rheumatology, Rady Children's Hospital of San Diego, University of California, San Diego, San Diego, CA, USA.

Harini Sampath (H)

Department of Nutritional Sciences and New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ 08901, USA.

Wei Ying (W)

Division of Endocrinology & Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.

Hal M Hoffman (HM)

Division of Pediatric Allergy, Immunology, and Rheumatology, Rady Children's Hospital of San Diego, University of California, San Diego, San Diego, CA, USA.

Gerald S Shadel (GS)

Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Michael Karin (M)

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Oxidized DNA fragments exit mitochondria via...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › ADN mitochondrial › Oxidized DNA fragments exit mitochondria via...
questionsmedicales.fr › Structures macromoléculaires › Complexes multiprotéiques › Inflammasomes › Oxidized DNA fragments exit mitochondria via...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interférons › Oxidized DNA fragments exit mitochondria via...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Oxidized DNA fragments exit mitochondria via...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › Oxidized DNA fragments exit mitochondria via...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines mitochondriales › Protéines de transport de la membrane mitochondriale › Pore de transition de perméabilité mitochondriale › Oxidized DNA fragments exit mitochondria via...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Protéines NLR › Protéine-3 de la famille des NLR contenant un domaine pyrine › Oxidized DNA fragments exit mitochondria via...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › Oxidized DNA fragments exit mitochondria via...