Oxidized mitochondrial DNA: a protective signal gone awry

• Published in: Trends in immunology Vol. 44; no. 3; pp. 188 - 200
• Main Authors: Xian, Hongxu, Karin, Michael
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2023
• Subjects: autoimmunity; cell-free DNA; cGAS–STING; DNA, Mitochondrial; Humans; Immunity, Innate; immunopathology; Inflammasomes; inflammation; Mitochondria; NLRP3 inflammasome; Ox-mtDNA; Signal Transduction - physiology; stressed mitochondria; immunopathology; autoimmunity; Ox-mtDNA; stressed mitochondria; inflammation; cGAS–STING; cell-free DNA; NLRP3 inflammasome
• ISSN: 1471-4906; 1471-4981; 1471-4981
• DOI: 10.1016/j.it.2023.01.006

Prokaryotic in origin, mitochondrial DNA (mtDNA) housed in eukaryotic cells exists within an oxidative environment and is subject to inefficient damage repair.Present at high copy number, mtDNA is an abundant source of stress-induced alarmins.mtDNA released from stressed mammalian mitochondria is likely to be oxidized and cleaved by flap structure-specific endonuclease 1 (FEN1).Oxidized (Ox)-mtDNA release depends on the opening of mitochondrial pores.Liberated Ox-mtDNA fragments engage different pattern recognition receptors depending on their location (cytoplasm, endosome, or extracellular space) to trigger proinflammatory and type I interferon (IFN) responses that are either beneficial or can ignite human autoimmunity and chronic inflammation. The immunoregulatory functions of mitochondria – key players in innate immunity – can depend on the generation of oxidized mitochondrial DNA (Ox-mtDNA) which escapes to the cytosol and activates the NLRP3 inflammasome and cGAS–STING signaling. Ox-mtDNA also enters the circulation, thus amplifying the initial inflammation. Although the sterile inflammatory response activated by Ox-mtDNA is beneficial in nature, sustained circulating Ox-mtDNA is detected in diverse auto-immunopathologies, potentially acting as a pathogenic driver. 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-1β, 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.