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<p>Mitochondria play a&#xa0;core role in maintaining neuronal homeostasis, especially in the regulation of mitochondrial calcium homeostasis. The mitochondrial calcium uniporter (MCU) complex and the regulatory factor Histidine triad nucleotide-binding protein&#xa0;2 (HINT2) are considered to be closely related to neuronal injury. To explore the mechanism of the HINT2-MCU-MICU1 axis in neuronal hypoxia injury, this study used the human neuroblastoma cell line SH-SY5Y to establish normal and hypoxia/reoxygenation injury models. The effects of MCU activity regulation on mitochondrial calcium homeostasis, cell activity and related gene expression were systematically evaluated by drug intervention and HINT2 overexpression. The results showed that under normal physiological conditions, MCU inhibitors or HINT2 overexpression upregulated HINT2 and MICU1 expression, downregulated MCU expression, reduced intracellular and mitochondrial calcium concentrations, enhanced mitochondrial membrane potential, reduced mitochondrial ROS levels and significantly improved cell viability. And MCU agonists exhibited the opposite effect. Under hypoxic conditions, MCU inhibitors or HINT2 overexpression alleviated calcium overload, increased mitochondrial membrane potential, reduced ROS generation and significantly inhibited cell apoptosis, while MCU agonists exacerbated hypoxia-induced calcium overload, mitochondrial dysfunction and apoptosis. This study revealed that HINT2 may exert neuroprotective effects by regulating MCU complex to regulate mitochondrial calcium homeostasis, and the HINT2-MCU-MICU1 axis is expected to become a&#xa0;potential therapeutic target for neurological diseases.</p>

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The protective role of HINT2 in hypoxia injury of neuroblastoma cells and its regulatory mechanism on MCU-MICU1 pathway

  • 期刊论文

  • 发表日期：

    2025年12月1日

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  • Shao Rui,
  • Zhang Lilong,
  • Geng Yannan,
  • Xu Tiantong

摘要

Mitochondria play a core role in maintaining neuronal homeostasis, especially in the regulation of mitochondrial calcium homeostasis. The mitochondrial calcium uniporter (MCU) complex and the regulatory factor Histidine triad nucleotide-binding protein 2 (HINT2) are considered to be closely related to neuronal injury. To explore the mechanism of the HINT2-MCU-MICU1 axis in neuronal hypoxia injury, this study used the human neuroblastoma cell line SH-SY5Y to establish normal and hypoxia/reoxygenation injury models. The effects of MCU activity regulation on mitochondrial calcium homeostasis, cell activity and related gene expression were systematically evaluated by drug intervention and HINT2 overexpression. The results showed that under normal physiological conditions, MCU inhibitors or HINT2 overexpression upregulated HINT2 and MICU1 expression, downregulated MCU expression, reduced intracellular and mitochondrial calcium concentrations, enhanced mitochondrial membrane potential, reduced mitochondrial ROS levels and significantly improved cell viability. And MCU agonists exhibited the opposite effect. Under hypoxic conditions, MCU inhibitors or HINT2 overexpression alleviated calcium overload, increased mitochondrial membrane potential, reduced ROS generation and significantly inhibited cell apoptosis, while MCU agonists exacerbated hypoxia-induced calcium overload, mitochondrial dysfunction and apoptosis. This study revealed that HINT2 may exert neuroprotective effects by regulating MCU complex to regulate mitochondrial calcium homeostasis, and the HINT2-MCU-MICU1 axis is expected to become a potential therapeutic target for neurological diseases.