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Mitochondria are descendants of endosymbiotic bacteria and retain essential prokaryotic features such as a compact circular genome. Consequently, in mammals, mitochondrial DNA is subjected to bidirectional transcription that generates overlapping transcripts, which are capable of forming long double-stranded RNA structures1,2. However, to our knowledge, mitochondrial double-stranded RNA has not been previously characterized in vivo. Here we describe the presence of a highly unstable native mitochondrial double-stranded RNA species at single-cell level and identify key roles for the degradosome components mitochondrial RNA helicase SUV3 and polynucleotide phosphorylase PNPase in restricting the levels of mitochondrial double-stranded RNA. Loss of either enzyme results in massive accumulation of mitochondrial double-stranded RNA that escapes into the cytoplasm in a PNPase-dependent manner. This process engages an MDA5-driven antiviral signalling pathway that triggers a type I interferon response. Consistent with these data, patients carrying hypomorphic mutations in the gene PNPT1, which encodes PNPase, display mitochondrial double-stranded RNA accumulation coupled with upregulation of interferon-stimulated genes and other markers of immune activation. The localization of PNPase to the mitochondrial inter-membrane space and matrix suggests that it has a dual role in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This in turn prevents the activation of potent innate immune defence mechanisms that have evolved to protect vertebrates against microbial and viral attack.

Original publication

DOI

10.1038/s41586-018-0363-0

Type

Journal article

Journal

Nature

Publication Date

08/2018

Volume

560

Pages

238 - 242

Keywords

Animals, DEAD-box RNA Helicases, Endoribonucleases, Exoribonucleases, Gene Expression Regulation, HeLa Cells, Herpesvirus 1, Human, Humans, Interferon Type I, Interferon-Induced Helicase, IFIH1, Mice, Mice, Inbred C57BL, Multienzyme Complexes, Mutation, Polyribonucleotide Nucleotidyltransferase, RNA Helicases, RNA, Double-Stranded, RNA, Mitochondrial, Single-Cell Analysis, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein