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Nature. 2018 Aug;560(7717):238-242. doi: 10.1038/s41586-018-0363-0. Epub 2018 Jul 25.

Mitochondrial double-stranded RNA triggers antiviral signalling in humans.

Author information

1
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. ashish.dhir@path.ox.ac.uk.
2
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
3
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
4
Faculty of Biology, University of Warsaw, Warsaw, Poland.
5
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
6
INSERM UMR1163, Institut Imagine, Paris, France.
7
Paris Descartes University, Sorbonne-Paris-Cité, Institut Imagine, Paris, France.
8
Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
9
Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
10
Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France.
11
INSERM U1223, Paris, France.
12
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
13
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland. rszczesny@ibb.waw.pl.
14
Faculty of Biology, University of Warsaw, Warsaw, Poland. rszczesny@ibb.waw.pl.
15
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. nicholas.proudfoot@path.ox.ac.uk.

Abstract

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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PMID:
30046113
PMCID:
PMC6570621
DOI:
10.1038/s41586-018-0363-0
[Indexed for MEDLINE]
Free PMC Article

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