Mitochondrial double-stranded RNA triggers antiviral signalling in humans
Open accessAbstract
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 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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Defective RNAse degradation causes double-stranded mtRNA accumulation in mitochondria, cytosolic leakage, and type I interferon production.
“defective degradation leads to double-stranded mtRNA accumulation in the organelle, subsequent cytosolic leakage of double-stranded mtRNA and type I interferon production150.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [150]
The paper reports that loss of either mitochondrial RNA degradosome component causes double-stranded mtRNA accumulation. However, its discussion of dsRNA localization and IFNB1 induction distinguishes the two: PNPase depletion permits cytosolic release and a type I interferon response, whereas SUV3 depletion leaves the RNA restricted to mitochondria without that response. The claim is therefore too broad if 'defective degradation' includes both defects. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSome evidence supports existence of unstable double-stranded mtRNA during homeostasis.
“although mtDNA transcription points towards the production of single-stranded mtRNA, some evidence supports the existence of unstable double-stranded mtRNA during homeostasis150.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [150]
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- Authors
- Dhir, A., Dhir, S., Borowski, L. S., Jimenez, L., Teitell, M., Rötig, A., Crow, Y. J., Rice, G. I., Duffy, D., Tamby, C., Nojima, T., Munnich, A., Schiff, M., de Almeida, C. R., Rehwinkel, J., Dziembowski, A., Szczesny, R. J., & Proudfoot, N. J.
- Affiliations
- University of Oxford (GB)
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences (PL)
- University of California, Los Angeles (US)
- Inserm (FR)
- University of Manchester (GB)
- Corresponding author
- Dhir, Ashish
- Proudfoot, Nicholas J.
- ORCID
- Venue
- Nature
- Published
- 2018-07-25
- Volume
- 560
- Issue
- 7717
- Pages
- 238-242
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6570621
- OpenAlex
- W2883018577
- Cited by
- 631
- References
- 41
- Citations by year
- 2026: 90 · 2025: 77 · 2024: 100 · 2023: 78 · 2022: 82 · 2021: 80 · 2020: 58 · 2019: 49 · 2018: 14
- FWCI
- 21.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc)
- Funders
- Wellcome Trust (107928, 107928/Z/15/Z)
- European Commission (POIG.02.02.00-14-024/08, POIG.02.02.00-14-024/08-00)
- Agence Nationale de la Recherche (ANR-10-IAHU- 01, ANR-16-CE17-0010, ANR-10-IAHU-0001, 10-IAHU-01, ANR-10, CE17001002)
- Narodowym Centrum Nauki
- National Institutes of Health (ANR-10-IAHU-01)
- Medical Research Council (MC_UU_00008/8)
- Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0428, BBS/E/B/000C0427)
- European Regional Development Fund (02.02.00-14-024/08-00, POIG.02.02.00-14-024/08, POIG.02.02.00-14-024/08-00)
- National Institute of General Medical Sciences (R01GM073981, GM073981, R01GM114188)
- FP7 Ideas: European Research Council (309449, 339270)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- mitochondrial double-stranded RNA, mitochondrial DNA, bidirectional transcription, antiviral signaling, MDA5, type I interferon response, polynucleotide phosphorylase, PNPT1, degradosome, innate immunity, interferon-stimulated genes, mitochondrial matrix
- MeSH terms
- Interferon-Induced Helicase, IFIH1, RNA, Mitochondrial, Animals, Endoribonucleases, Exoribonucleases, Gene Expression Regulation, HeLa Cells, Humans, Interferon Type I, Mice, Inbred C57BL, Multienzyme Complexes, Mutation, Polyribonucleotide Nucleotidyltransferase, RNA, Double-Stranded, Herpesvirus 1, Human, RNA Helicases, Mitochondrial Proteins, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mice, DEAD-box RNA Helicases, Single-Cell Analysis
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