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Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype

Author

Listed:
  • Han-Yi Chen

    (National Taiwan University)

  • Wan-Chen Hsieh

    (National Tsing Hua University)

  • Yu-Chieh Liu

    (National Taiwan University)

  • Huei-Ying Li

    (National Taiwan University)

  • Po-Yo Liu

    (National Taiwan University)

  • Yu-Ting Hsu

    (National Taiwan University)

  • Shao-Chun Hsu

    (National Taiwan University)

  • An-Chi Luo

    (National Taiwan University)

  • Wei-Chen Kuo

    (National Taiwan University)

  • Yi-Jhen Huang

    (National Taiwan University)

  • Gan-Guang Liou

    (National Taiwan University)

  • Meng-Yun Lin

    (National Taiwan University)

  • Chun-Jung Ko

    (National Taiwan University)

  • Hsing-Chen Tsai

    (National Taiwan University
    National Taiwan University Hospital
    National Taiwan University Hospital)

  • Shu-Jung Chang

    (National Taiwan University)

Abstract

Bacterial genotoxins damage host cells by targeting their chromosomal DNA. In the present study, we demonstrate that a genotoxin of Salmonella Typhi, typhoid toxin, triggers the senescence-associated secretory phenotype (SASP) by damaging mitochondrial DNA. The actions of typhoid toxin disrupt mitochondrial DNA integrity, leading to mitochondrial dysfunction and disturbance of redox homeostasis. Consequently, it facilitates the release of damaged mitochondrial DNA into the cytosol, activating type I interferon via the cGAS-STING pathway. We also reveal that the GCN2-mediated integrated stress response plays a role in the upregulation of inflammatory components depending on the STING signaling axis. These SASP factors can propagate the senescence effect on T cells, leading to senescence in these cells. These findings provide insights into how a bacterial genotoxin targets mitochondria to trigger a proinflammatory SASP, highlighting a potential therapeutic target for an anti-toxin intervention.

Suggested Citation

  • Han-Yi Chen & Wan-Chen Hsieh & Yu-Chieh Liu & Huei-Ying Li & Po-Yo Liu & Yu-Ting Hsu & Shao-Chun Hsu & An-Chi Luo & Wei-Chen Kuo & Yi-Jhen Huang & Gan-Guang Liou & Meng-Yun Lin & Chun-Jung Ko & Hsing-, 2024. "Mitochondrial injury induced by a Salmonella genotoxin triggers the proinflammatory senescence-associated secretory phenotype," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47190-y
    DOI: 10.1038/s41467-024-47190-y
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    References listed on IDEAS

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    1. Alfiya Akhmetshina & Katrin Palumbo & Clara Dees & Christina Bergmann & Paulius Venalis & Pawel Zerr & Angelika Horn & Trayana Kireva & Christian Beyer & Jochen Zwerina & Holm Schneider & Anika Sadows, 2012. "Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    2. Jeongmin Song & Xiang Gao & Jorge E. Galán, 2013. "Structure and function of the Salmonella Typhi chimaeric A2B5 typhoid toxin," Nature, Nature, vol. 499(7458), pages 350-354, July.
    3. Casey C. Fowler & Gabrielle Stack & Xuyao Jiao & Maria Lara-Tejero & Jorge E. Galán, 2019. "Alternate subunit assembly diversifies the function of a bacterial toxin," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    4. Dominik Saul & Robyn Laura Kosinsky & Elizabeth J. Atkinson & Madison L. Doolittle & Xu Zhang & Nathan K. LeBrasseur & Robert J. Pignolo & Paul D. Robbins & Laura J. Niedernhofer & Yuji Ikeno & Diana , 2022. "A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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