Nuclear sensing of mitochondrial DNA breaks enhances immune surveillance

Published on Aug 3, 2021in bioRxiv
· DOI :10.17632/JSZD6BWVTW.1
Agnel Sfeir23
Estimated H-index: 23
(NYU: New York University),
M. Tigano (NYU: New York University)+ -2 AuthorsYi Fu5
Estimated H-index: 5
(NYU: New York University)
Sources
Abstract
Mitochondrial double-strand breaks (mtDSBs) are toxic lesions that compromise mitochondrial function. Mito-nuclear communication is essential to maintain cellular homeostasis, however, the nuclear response to mtDSBs remains unknown. Using mitochondrial-targeted TALENs, we show that mtDSBs activate a type I interferon response evidenced by phosphorylation of STAT1 and activation of interferon stimulated genes (ISG). Following mtDNA break formation, BAK-BAX mediated herniation releases mitochondrial RNA to the cytoplasm and trigger a RIG-I/MAVS-dependent immune response. In an independent set of experiments, we investigate the role of mtDSBs in interferon signaling due to genotoxic stress. Our data reveal that activation of ISGs is greatly diminished when cells lacking mtDNA are exposed to ionizing radiation. Furthermore, we show that mtDNA breaks synergize with nuclear DNA damage to mount a robust interferon response. In conclusion, cytoplasmic accumulation of mitochondrial RNA is as an intrinsic immune surveillance mechanism for cells to cope with mtDSBs, including ones inflicted by genotoxic agents.
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