Oxidized mitochondrial DNA: a protective signal gone awry

Despite the emergence of mitochondria as key regulators of innate immunity, the mechanisms underlying the generation and release of immunostimulatory alarmins by stressed mitochondria remains nebulous. We propose that the major mitochondrial alarmin in myeloid cells is oxidized mitochondrial DNA (Ox-mtDNA). Fragmented Ox-mtDNA enters the cytosol where it activates the NLRP3 inflammasome and generates IL-1 beta, IL-18, and cGAS-STING to induce type I interferons and interferon-stimulated genes. Inflammasome activation further enables the circulatory release of Ox-mtDNA by opening gasdermin D pores. We summarize new data showing that, in addition to being an autoimmune disease biomarker, Ox-mtDNA converts beneficial transient inflammation into long-lasting immunopathology. We discuss how Ox-mtDNA induces short- and long-term immune activation, and highlight its homeostatic and immunopathogenic functions.

Automated summary

Research has found that oxidized mitochondrial DNA (Ox-mtDNA) in myeloid cells activates the NLRP3 inflammasome, leading to the production of pro-inflammatory cytokines and interferons. In addition, Ox-mtDNA can be released into circulation through gasdermin D pores. Furthermore, Ox-mtDNA can convert transient inflammation into long-term immunopathology and serve as a biomarker for autoimmune diseases.