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Mitochondrial double-stranded RNA triggers antiviral signalling in humans

Author

Listed:
  • Ashish Dhir

    (University of Oxford)

  • Somdutta Dhir

    (University of Oxford)

  • Lukasz S. Borowski

    (Polish Academy of Sciences
    University of Warsaw)

  • Laura Jimenez

    (University of California, Los Angeles)

  • Michael Teitell

    (University of California, Los Angeles)

  • Agnès Rötig

    (INSERM UMR1163, Institut Imagine)

  • Yanick J. Crow

    (INSERM UMR1163, Institut Imagine
    Sorbonne-Paris-Cité, Institut Imagine
    MRC Institute of Genetics and Molecular Medicine, University of Edinburgh)

  • Gillian I. Rice

    (School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester)

  • Darragh Duffy

    (Immunobiology of Dendritic Cells, Institut Pasteur
    INSERM U1223)

  • Christelle Tamby

    (INSERM UMR1163, Institut Imagine)

  • Takayuki Nojima

    (University of Oxford)

  • Arnold Munnich

    (INSERM UMR1163, Institut Imagine)

  • Manuel Schiff

    (INSERM UMR1163, Institut Imagine)

  • Claudia Ribeiro Almeida

    (University of Oxford)

  • Jan Rehwinkel

    (University of Oxford)

  • Andrzej Dziembowski

    (Polish Academy of Sciences
    University of Warsaw)

  • Roman J. Szczesny

    (Polish Academy of Sciences
    University of Warsaw)

  • Nicholas J. Proudfoot

    (University of Oxford)

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.

Suggested Citation

  • Ashish Dhir & Somdutta Dhir & Lukasz S. Borowski & Laura Jimenez & Michael Teitell & Agnès Rötig & Yanick J. Crow & Gillian I. Rice & Darragh Duffy & Christelle Tamby & Takayuki Nojima & Arnold Munnic, 2018. "Mitochondrial double-stranded RNA triggers antiviral signalling in humans," Nature, Nature, vol. 560(7717), pages 238-242, August.
  • Handle: RePEc:nat:nature:v:560:y:2018:i:7717:d:10.1038_s41586-018-0363-0
    DOI: 10.1038/s41586-018-0363-0
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    Cited by:

    1. Yujie Zhu & Mingchao Zhang & Weiran Wang & Shuang Qu & Minghui Liu & Weiwei Rong & Wenwen Yang & Hongwei Liang & Caihong Zeng & Xiaodong Zhu & Limin Li & Zhihong Liu & Ke Zen, 2023. "Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Abhishek Aich & Angela Boshnakovska & Steffen Witte & Tanja Gall & Kerstin Unthan-Fechner & Roya Yousefi & Arpita Chowdhury & Drishan Dahal & Aditi Methi & Svenja Kaufmann & Ivan Silbern & Jan Prochaz, 2024. "Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Shane T. Killarney & Rachel Washart & Ryan S. Soderquist & Jacob P. Hoj & Jamie Lebhar & Kevin H. Lin & Kris C. Wood, 2023. "Executioner caspases restrict mitochondrial RNA-driven Type I IFN induction during chemotherapy-induced apoptosis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Vanessa López-Polo & Mate Maus & Emmanouil Zacharioudakis & Miguel Lafarga & Camille Stephan-Otto Attolini & Francisco D. M. Marques & Marta Kovatcheva & Evripidis Gavathiotis & Manuel Serrano, 2024. "Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Yue Wang & Dhamotharan Pattarayan & Haozhe Huang & Yueshan Zhao & Sihan Li & Yifei Wang & Min Zhang & Song Li & Da Yang, 2024. "Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Elina Idiiatullina & Mahmoud Al-Azab & Meng Lin & Katja Hrovat-Schaale & Ziyang Liu & Xiaotian Li & Caiqin Guo & Xixi Chen & Yaoying Li & Song Gao & Jun Cui & Wenhao Zhou & Li Liu & Yuxia Zhang & Seth, 2024. "Heterozygous de novo dominant negative mutation of REXO2 results in interferonopathy," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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