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<p>Pathogenic bacteria frequently manipulate host cell death pathways to facilitate infection, though the precise mechanisms remain elusive. Here, we demonstrate that pathogenic <i>Escherichia coli</i> disrupts copper homeostasis through upregulation of copper transporter CTR2, thereby triggering cuproptosis to drive infectious pathology. During infection, circulating lipopolysaccharide activates the morphological hallmarks of cuproptosis via the gut–LPS–liver axis. Furthermore, mitochondrial malate dehydrogenase 2 (MDH2) functions as a transcriptional regulator, triggering CTR2 expression and metabolic reprogramming via acetylation-dependent nuclear translocation in response to infection. Notably, inhibiting cuproptosis mitigates liver damage caused by infection, highlighting its critical role in pathogen-host interactions. These findings identify a mechanism underlying <i>E. coli</i> pathogenesis and support therapeutic approaches based on targeted modulation of metal-dependent cell death.</p>

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Acetylated mitochondrial MDH2 regulates CTR2 transcription to induce cuproptosis during Escherichia coli infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Hao Wang,
  • Peng Xiao,
  • Liping Chen,
  • Meng Zhou,
  • Jingsong Zhang,
  • Jinlong Xiao,
  • Ru Zhao,
  • Jingang Zhao,
  • Tianling Pan,
  • Jue Sheng,
  • Yue Li,
  • Jinzhi Ma,
  • Longbao Lv,
  • Yulin Yan,
  • Hong Gao

摘要

Pathogenic bacteria frequently manipulate host cell death pathways to facilitate infection, though the precise mechanisms remain elusive. Here, we demonstrate that pathogenic Escherichia coli disrupts copper homeostasis through upregulation of copper transporter CTR2, thereby triggering cuproptosis to drive infectious pathology. During infection, circulating lipopolysaccharide activates the morphological hallmarks of cuproptosis via the gut–LPS–liver axis. Furthermore, mitochondrial malate dehydrogenase 2 (MDH2) functions as a transcriptional regulator, triggering CTR2 expression and metabolic reprogramming via acetylation-dependent nuclear translocation in response to infection. Notably, inhibiting cuproptosis mitigates liver damage caused by infection, highlighting its critical role in pathogen-host interactions. These findings identify a mechanism underlying E. coli pathogenesis and support therapeutic approaches based on targeted modulation of metal-dependent cell death.