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.
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We acknowledge V. Bondet for CSF IFNα data. We also thank E. Johnson and A. Pielach from the Dunn School Bioimaging facility for electron microscopy work and M. Alexeyev for sharing plasmids encoding UL12.5M185 and mUNG1 (Addgene #70109 and #70110, respectively). This work was supported by funding to N.J.P. (Wellcome Trust Investigator Award (107928|Z|15|Z), ERC Advanced Grant (339270)) and to M.T. (National Institutes of Health (NIH) (GM073981)). Y.J.C. acknowledges funding from the European Research Council (GA 309449: fellowship), a state subsidy managed by the National Research Agency (ANR, France) under the Investments for the Future (ANR-10-IAHU-01), and an ANR grant CE17001002 to Y.J.C. and D.D. Y.J.C. and D.D. thank ImmunoQure AG for sharing of the antibodies used to assess IFNα protein levels in the Simoa assay. Studies were supported by grant 2014/13/D/NZ2/01114 (to R.J.S.) from the National Science Centre, Poland. Experiments were carried out with the use of CePT infrastructure financed by the European Union through the European Regional Development Fund (Innovative economy 2007–13, Agreement POIG.02.02.00-14-024/08-00).
Nature thanks C. Reis e Sousa, S. Riis Paludan, G. Shadel and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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