Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance

• Published in: Nature (London) 2021-03, Vol.591 (7850), p.477-481
• Main Authors: Tigano, Marco, Vargas, Danielle C., Tremblay-Belzile, Samuel, Fu, Yi, Sfeir, Agnel
• Format: Article
• Language: English
• Subjects: 14/19; 14/63; 38/22; 38/90; 38/91; 42; 45; 45/29; 45/41; 45/88; 631/337/1427/2122; 631/80/642/333/1465; Adaptor Proteins, Signal Transducing - metabolism; bcl-2 Homologous Antagonist-Killer Protein - metabolism; bcl-2-Associated X Protein - metabolism; Cell Line; Cells, Cultured; Communication; Cytoplasm; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded - radiation effects; DNA damage; DNA, Mitochondrial - immunology; DNA, Mitochondrial - radiation effects; Gamma irradiation; Genes; Genetic aspects; Genomes; Genotoxic chemicals; Genotoxicity; Homeostasis; Humanities and Social Sciences; Humans; Immune response; Immune response (cell-mediated); Immune system; Immunity, Innate - immunology; Immunosurveillance; Interferon; Ionizing radiation; Irradiation; Kinases; Mitochondria; Mitochondria - immunology; Mitochondria - radiation effects; Mitochondrial DNA; multidisciplinary; Nuclease; Paracrine Communication; Phosphorylation; Physiological aspects; Radiation; Radiation, Ionizing; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sensors; Stat1 protein; Surveillance; Synergism; Transcription activation; Transcription activator-like effector nucleases; Transcription, Genetic; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03269-w

Mitochondrial DNA double-strand breaks (mtDSBs) are toxic lesions that compromise the integrity of mitochondrial DNA (mtDNA) and alter mitochondrial function 1 . Communication between mitochondria and the nucleus is essential to maintain cellular homeostasis; however, the nuclear response to mtDSBs remains unknown 2 . Here, using mitochondrial-targeted transcription activator-like effector nucleases (TALENs) 1 , 3 , 4 , we show that mtDSBs activate a type-I interferon response that involves the phosphorylation of STAT1 and activation of interferon-stimulated genes. After the formation of breaks in the mtDNA, herniation 5 mediated by BAX and BAK releases mitochondrial RNA into the cytoplasm and triggers a RIG-I–MAVS-dependent immune response. We further investigated the effect of mtDSBs on interferon signalling after treatment with ionizing radiation and found a reduction in the activation of interferon-stimulated genes when cells that lack mtDNA are exposed to gamma irradiation. We also show that mtDNA breaks synergize with nuclear DNA damage to mount a robust cellular immune response. Taken together, we conclude that cytoplasmic accumulation of mitochondrial RNA is an intrinsic immune surveillance mechanism for cells to cope with mtDSBs, including breaks produced by genotoxic agents. Breaks in mitochondrial DNA cause leakage of mitochondrial RNA into the cytoplasm, enhancing immune surveillance and synergizing with nuclear DNA damage to mount a robust type-I interferon immune response.