Scholarlink

<p>Mitochondrial cristae ultrastructure enables ATP synthase organization for adaptive energy production. This process is critical for regulating microglia mediated neuroinflammation in ischemic stroke pathology. However, therapeutic strategies targeting cristae remodeling remain unexplored. We identified a chemical probe, icariin II (ICS), which restores mitochondrial cristae by targeting triose phosphate isomerase 1 (TPI1). ICS-induced TPI1 conformational switching recruits ATP5MF to drive F<sub>1</sub>F<sub>o</sub>-ATP synthase dimerization, thereby resulting in cardiolipin-mediated membrane curvature generation for cristae morphogenesis. Functionally, TPI1-targeted intervention reprograms microglial immunometabolism by rescuing oxidative phosphorylation, suppressing mtDNA-STING neuroinflammation, and promoting M2 polarization. In vivo, pharmacologically targeting TPI1 inhibits microglial activation to reverse the pathological processes in a middle cerebral artery occlusion rat model (male only). Further, evidence from stroke patients suggests an association between TPI1 and microglial activation. Collectively, our findings reveal that cristae plasticity is a promising therapeutic target for mitochondrial disorders, with TPI1 as a central regulator for ischemic stroke.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Triose phosphate isomerase 1 remodels mitochondrial cristae ultrastructure to rewire microglial immunometabolism against ischemic stroke

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月7日

查看全文
  • Xiao-Wen Zhang,
  • Xiao-Ming Ye,
  • Ran Wang,
  • Yong-Dong Guo,
  • Ling Li,
  • Yang Chen,
  • Ting-ting Liu,
  • Xiao-Qing Zhou,
  • Yu-Qi Wang,
  • Zhong-Yao Li,
  • Zhi-Yuan Lu,
  • Zhi-Yong Du,
  • Wei Zhou,
  • Bo Han,
  • Peng-Fei Tu,
  • Qi-Xin Chen,
  • Chun-Hong Zheng,
  • Ke-Wu Zeng

摘要

Mitochondrial cristae ultrastructure enables ATP synthase organization for adaptive energy production. This process is critical for regulating microglia mediated neuroinflammation in ischemic stroke pathology. However, therapeutic strategies targeting cristae remodeling remain unexplored. We identified a chemical probe, icariin II (ICS), which restores mitochondrial cristae by targeting triose phosphate isomerase 1 (TPI1). ICS-induced TPI1 conformational switching recruits ATP5MF to drive F1Fo-ATP synthase dimerization, thereby resulting in cardiolipin-mediated membrane curvature generation for cristae morphogenesis. Functionally, TPI1-targeted intervention reprograms microglial immunometabolism by rescuing oxidative phosphorylation, suppressing mtDNA-STING neuroinflammation, and promoting M2 polarization. In vivo, pharmacologically targeting TPI1 inhibits microglial activation to reverse the pathological processes in a middle cerebral artery occlusion rat model (male only). Further, evidence from stroke patients suggests an association between TPI1 and microglial activation. Collectively, our findings reveal that cristae plasticity is a promising therapeutic target for mitochondrial disorders, with TPI1 as a central regulator for ischemic stroke.