IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v591y2021i7850d10.1038_s41586-021-03269-w.html
   My bibliography  Save this article

Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance

Author

Listed:
  • Marco Tigano

    (NYU School of Medicine
    Memorial Sloan Kettering Cancer Center)

  • Danielle C. Vargas

    (NYU School of Medicine)

  • Samuel Tremblay-Belzile

    (NYU School of Medicine
    Memorial Sloan Kettering Cancer Center)

  • Yi Fu

    (NYU School of Medicine
    Memorial Sloan Kettering Cancer Center)

  • Agnel Sfeir

    (NYU School of Medicine
    Memorial Sloan Kettering Cancer Center)

Abstract

Mitochondrial DNA double-strand breaks (mtDSBs) are toxic lesions that compromise the integrity of mitochondrial DNA (mtDNA) and alter mitochondrial function1. Communication between mitochondria and the nucleus is essential to maintain cellular homeostasis; however, the nuclear response to mtDSBs remains unknown2. Here, using mitochondrial-targeted transcription activator-like effector nucleases (TALENs)1,3,4, we show that mtDSBs activate a type-I interferon response that involves the phosphorylation of STAT1 and activation of interferon-stimulated genes. After the formation of breaks in the mtDNA, herniation5 mediated by BAX and BAK releases mitochondrial RNA into the cytoplasm and triggers a RIG-I–MAVS-dependent immune response. We further investigated the effect of mtDSBs on interferon signalling after treatment with ionizing radiation and found a reduction in the activation of interferon-stimulated genes when cells that lack mtDNA are exposed to gamma irradiation. We also show that mtDNA breaks synergize with nuclear DNA damage to mount a robust cellular immune response. Taken together, we conclude that cytoplasmic accumulation of mitochondrial RNA is an intrinsic immune surveillance mechanism for cells to cope with mtDSBs, including breaks produced by genotoxic agents.

Suggested Citation

  • Marco Tigano & Danielle C. Vargas & Samuel Tremblay-Belzile & Yi Fu & Agnel Sfeir, 2021. "Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance," Nature, Nature, vol. 591(7850), pages 477-481, March.
  • Handle: RePEc:nat:nature:v:591:y:2021:i:7850:d:10.1038_s41586-021-03269-w
    DOI: 10.1038/s41586-021-03269-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-021-03269-w
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-021-03269-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. Niranjana Natarajan & Jonathan Florentin & Ebin Johny & Hanxi Xiao & Scott Patrick O’Neil & Liqun Lei & Jixing Shen & Lee Ohayon & Aaron R. Johnson & Krithika Rao & Xiaoyun Li & Yanwu Zhao & Yingze Zh, 2024. "Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Naijun Miao & Zhuning Wang & Qinlan Wang & Hongyan Xie & Ninghao Yang & Yanzhe Wang & Jin Wang & Haixia Kang & Wenjuan Bai & Yuanyuan Wang & Rui He & Kepeng Yan & Yang Wang & Qiongyi Hu & Zhaoyuan Liu, 2023. "Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. 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.
    5. 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.
    6. Lulu Ren & Jianqin Wan & Xiaoyan Li & Jie Yao & Yan Ma & Fanchao Meng & Shusen Zheng & Weidong Han & Hangxiang Wang, 2024. "Mitochondrial rewiring with small-molecule drug-free nanoassemblies unleashes anticancer immunity," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:591:y:2021:i:7850:d:10.1038_s41586-021-03269-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.