Editors' ChoiceCell Biology

Sensing mitochondrial damage

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Science Signaling  23 Mar 2021:
Vol. 14, Issue 675, eabi6106
DOI: 10.1126/scisignal.abi6106

Detection of cytosolic mitochondrial RNA resulting from mitochondrial DNA breaks triggers a type I interferon response.

Mitochondria are membrane-bound organelles that perform a central role in cellular metabolism, but they also act as platforms for the sensing of nucleic acids in the cytosol. Mitochondria contain several copies of mitochondrial DNA (mtDNA), which encode gene products involved in metabolism. Chemotherapeutic agents and ionizing radiation can cause double-stranded breaks in mtDNA (mtDSBs), which lead to mitochondrial dysfunction. Tigano et al. found that mtDSBs generated within distinct loci in human epithelial cells by mitochondria-directed TALENs induced many genes involved in the type I interferon (IFN) response and antiviral defense. Although the mitochondria with mtDSBs appeared to function normally, they underwent herniation caused by the formation of pores containing BAX and BAK. Depletion of the cytosolic RNA–sensing components RIG-I and MAVS, but not that of components of the DNA-sensing machinery, reduced the expression of IFN-stimulated genes (ISGs) in cells with mtDSBs. Treatment of mtDNA-replete MCF10A cells with ionizing radiation also resulted in mtDNA damage and ISG expression; however, this response was substantially decreased in irradiated, mtDNA-deficient cells. Furthermore, ISG expression in irradiated cells was reduced when BAX and BAK were depleted. Subcellular fractionation experiments showed the enrichment of mitochondrial RNA (mtRNA) in the cytoplasmic fractions of irradiated cells, and proximity labeling assays revealed the localization of mtRNA near RIG-I. Together, these data suggest that genotoxic stress exposes cytosolic sensors to mtRNA to trigger a type I IFN response. As Naresh and Haynes discuss in commentary, it would be interesting to determine whether this same pathway is also involved in autoimmunity.

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