Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance

Marco Tigano, Danielle C. Vargas, Samuel Tremblay-Belzile, Yi Fu and Agnel Sfeir ()
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Marco Tigano: NYU School of Medicine
Danielle C. Vargas: NYU School of Medicine
Samuel Tremblay-Belzile: NYU School of Medicine
Yi Fu: NYU School of Medicine
Agnel Sfeir: NYU School of Medicine

Nature, 2021, vol. 591, issue 7850, 477-481

Abstract: Abstract Mitochondrial DNA double-strand breaks (mtDSBs) are toxic lesions that compromise the integrity of mitochondrial DNA (mtDNA) and alter mitochondrial function1. Communication between mitochondria and the nucleus is essential to maintain cellular homeostasis; however, the nuclear response to mtDSBs remains unknown2. 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, herniation5 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.

Date: 2021
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DOI: 10.1038/s41586-021-03269-w

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