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<p>Mitochondrial dysfunction is a critical contributor to neuronal damage in acute ischemic stroke (AIS), and targeting mitochondrial function represents a promising therapeutic strategy. This study unveils the pivotal role of Cend1 protein in ischemic stroke and elucidates its underlying mechanisms. Using Cend1 knockout (KO) mice, Cend1 deficiency was shown to exacerbate cerebral ischemia/reperfusion injury, as evidenced by enlarged infarct volume, worsened neurological deficits in motor coordination and grip strength, together with alterations in mitochondrial membrane potential (ΔΨm), mPTP opening, ATP content, and the activities of respiratory Complex I and V. Mechanistically, Cend1 forms dimers via conserved GXXXA motifs in its transmembrane domain to enhance ATP synthesis. Disruption of dimerization of Cend1 (such as G130P mutation) destabilized Cend1, accelerating its degradation and abolishing ATP-enhancing effects. Atp5f1b, a mitochondrial ATP synthase subunit, was found to interact with Cend1. Furthermore, screening identified the small-molecule compound Tianeptine (TNT), which stabilizes Cend1 dimers, elevates ATP levels, and confers neuroprotection in a Cend1-dependent manner. Notably, TNT’s efficacy was abolished in Cend1 KO mice, highlighting its reliance on Cend1. The findings support the Cend1/Atp5f1b interaction as a potential mitochondria-targeted mechanism, offering innovative strategies to combat ischemic stroke by enhancing bioenergetic resilience.</p>

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Targeting Cend1-Atp5f1b interaction rescues mitochondrial dysfunction and ameliorates ischemic brain injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月31日

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  • Hao Li,
  • Yi Yang,
  • Meng Zhang,
  • Eric Guo,
  • Zeheng Li,
  • Bo Wan,
  • Zhigang Miao,
  • Wei Ge,
  • Gang Chen,
  • Xingshun Xu

摘要

Mitochondrial dysfunction is a critical contributor to neuronal damage in acute ischemic stroke (AIS), and targeting mitochondrial function represents a promising therapeutic strategy. This study unveils the pivotal role of Cend1 protein in ischemic stroke and elucidates its underlying mechanisms. Using Cend1 knockout (KO) mice, Cend1 deficiency was shown to exacerbate cerebral ischemia/reperfusion injury, as evidenced by enlarged infarct volume, worsened neurological deficits in motor coordination and grip strength, together with alterations in mitochondrial membrane potential (ΔΨm), mPTP opening, ATP content, and the activities of respiratory Complex I and V. Mechanistically, Cend1 forms dimers via conserved GXXXA motifs in its transmembrane domain to enhance ATP synthesis. Disruption of dimerization of Cend1 (such as G130P mutation) destabilized Cend1, accelerating its degradation and abolishing ATP-enhancing effects. Atp5f1b, a mitochondrial ATP synthase subunit, was found to interact with Cend1. Furthermore, screening identified the small-molecule compound Tianeptine (TNT), which stabilizes Cend1 dimers, elevates ATP levels, and confers neuroprotection in a Cend1-dependent manner. Notably, TNT’s efficacy was abolished in Cend1 KO mice, highlighting its reliance on Cend1. The findings support the Cend1/Atp5f1b interaction as a potential mitochondria-targeted mechanism, offering innovative strategies to combat ischemic stroke by enhancing bioenergetic resilience.