Oxidized mitochondrial DNA: a protective signal gone awry
1Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
Trends in Immunology
|February 4, 2023
Summary
Oxidized mitochondrial DNA (Ox-mtDNA) is a key alarmin in myeloid cells, activating inflammasomes and immune responses. This study reveals Ox-mtDNA
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Mitochondria play critical roles in innate immunity.
- Mechanisms of alarmin release from stressed mitochondria are unclear.
Purpose of the Study:
- Identify the primary mitochondrial alarmin in myeloid cells.
- Elucidate the pathways of Ox-mtDNA-mediated immune activation and release.
Main Methods:
- Investigated cytosolic entry of fragmented Ox-mtDNA.
- Assessed activation of NLRP3 inflammasome, cGAS-STING pathway.
- Analyzed IL-1β, IL-18, and type I interferon induction.
- Examined gasdermin D pore formation and Ox-mtDNA release.
Main Results:
- Oxidized mitochondrial DNA (Ox-mtDNA) is identified as the major alarmin.
- Ox-mtDNA activates NLRP3 inflammasome and cGAS-STING pathways.
- Gasdermin D pores facilitate circulatory release of Ox-mtDNA.
- Ox-mtDNA drives both short- and long-term immune activation.
Conclusions:
- Ox-mtDNA is a crucial mediator of innate immune responses originating from mitochondria.
- Ox-mtDNA contributes to the transition from transient inflammation to chronic immunopathology.
- Ox-mtDNA has dual roles in immune homeostasis and disease pathogenesis.
Keywords:
NLRP3 inflammasomeOx-mtDNAautoimmunitycGAS–STINGcell-free DNAimmunopathologyinflammationstressed mitochondriaMore Related Videos
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