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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
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    Citations

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    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    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.

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