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

Autor: Chen HY; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan., Hsieh WC; Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan., Liu YC; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan., Li HY; Medical Microbiota Center of the First Core Laboratory, College of Medicine, National Taiwan University, Taipei, Taiwan., Liu PY; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan., Hsu YT; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan., Hsu SC; Imaging Core, College of Medicine, National Taiwan University, Taipei, Taiwan., Luo AC; Imaging Core, College of Medicine, National Taiwan University, Taipei, Taiwan., Kuo WC; Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan., Huang YJ; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan., Liou GG; Cryo-EM Core, College of Medicine, National Taiwan University, Taipei, Taiwan., Lin MY; Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan., Ko CJ; Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan., Tsai HC; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.; Center for Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan., Chang SJ; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan. sjchang@ntu.edu.tw.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Mar 30; Vol. 15 (1), pp. 2778. Date of Electronic Publication: 2024 Mar 30.
DOI: 10.1038/s41467-024-47190-y
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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