期刊
NATURE
卷 560, 期 7717, 页码 238-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-018-0363-0
关键词
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资金
- mUNG1 [70109, 70110]
- Wellcome Trust Investigator Award [107928|Z|15|Z]
- ERC Advanced Grant [339270]
- National Institutes of Health (NIH) [GM073981]
- European Research Council [GA 309449]
- National Research Agency (ANR, France) under the Investments for the Future [ANR-10-IAHU-01]
- ANR [CE17001002]
- National Science Centre, Poland [2014/13/D/NZ2/01114]
- European Union through the European Regional Development Fund [POIG.02.02.00-14-024/08-00]
- Wellcome Trust [107928/Z/15/Z] Funding Source: Wellcome Trust
- European Research Council (ERC) [339270] Funding Source: European Research Council (ERC)
- BBSRC [BBS/E/B/000C0428, BBS/E/B/000C0427] Funding Source: UKRI
- MRC [MC_UU_12010/8, MC_UU_00008/8] Funding Source: UKRI
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 structures(1.2). 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 mitochondria' 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 up regulation 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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