Nuclear Sensing of Breaks in Mitochondrial DNA Enhances Immune Surveillance

Targeting Mitochondria 2021 sfeir-agnelDr. Agnel Sfeir from Memorial Sloan Kettering Cancer Center, USAwill give a presentation on :Nuclear Sensing of Breaks in Mitochondrial DNA Enhances Immune Surveillance"

Dr. Sfeir will describe mitochondrial DNA double-strand breaks (mtDSBs) as toxic lesions that compromise the integrity of mitochondrial DNA (mtDNA) and alter mitochondrial function. Communication between mitochondria and the nucleus is essential to maintain cellular homeostasis; however, the nuclear response to mtDSBs remains unknown. Here, using mitochondrial-targeted transcription activator-like effector nucleases (TALENs), 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 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.


Targeting Mitochondria 2021 Congress
October 27-29, 2021 - Berlin & Virtual Congress