Session Item

Mitochondrial DNA (mtDNA) double-strand breaks (DSBs) are toxic lesions that compromise mtDNA integrity and alter mitochondrial function. Mito-nuclear communication is essential to maintain cellular homeostasis. However, the nuclear response to mtDNA-DSBs remains unknown. Using mitochondrial-targeted TALENs, we show that mtDNA-DSBs activate a type I interferon response evidenced by phosphorylation of STAT1 and activation of interferon-stimulated genes (ISG). Following mtDNA break formation, BAX-BAK mediated herniation releases mitochondrial RNA to the cytoplasm and triggers a RIG-I/MAVS-dependent immune response. This retrograde signaling pathway was critical in mediating Type-I Interferon responses and paracrine signaling following ionizing radiation. Gamma radiation inflicted physical damage to mtDNA and caused loss of mitochondrial RNA granules, associated with Bax/Bak dependent mitochondrial herniation, the release of mitochondrial RNA in the cytosol, and activation of RIG-I/MAVS signaling axis. Accordingly, we also report diminished ISG activation when cells lacking mtDNA are exposed to gamma irradiation. Lastly, we show that mtDNA breaks synergize with nuclear DNA damage to mount a robust cellular immune response. Altogether, we conclude that cytoplasmic accumulation of mitochondrial RNA is an intrinsic immune surveillance mechanism for cells to cope with mtDSBs, including those inflicted by genotoxic agents.