Department of Anesthesiology, The First Medical Center of Chinese, PLA General Hospital, No.28, Fuxing road, Beijing, 100853, China.
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Beijing, 100850, China.
J Transl Med. 2024 Oct 28;22(1):974. doi: 10.1186/s12967-024-05780-w.
Brain damage caused by acute hypoxia is associated with the physiological activities of mitochondria. Although mitochondria being dynamically regulated, our comprehensive understanding of the response of specific brain cell types to acute hypoxia remains ambiguous. Tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial-based molecular chaperone, plays a role in controlling mitochondrial movements. Herein, we demonstrated that acute hypoxia significantly alters mitochondria morphology and functionality in both in vivo and in vitro brain injury experiments. Summary-data-based Mendelian Randomization (SMR) analyses revealed possible causative links between mitochondria-related genes and hypoxia injury. Advancing the protein-protein interaction network and molecular docking further elucidated the associations between TRAP1 and mitochondrial dynamics. Furthermore, it was shown that TRAP1 knockdown levels variably affected the expression of key mitochondrial dynamics proteins (DRP1, FIS1, and MFN1/2) in primary hippocampal neurons, astrocytes, and BV-2 cell, leading to changes in mitochondrial structure and function. Understanding the function of TRAP1 in altering mitochondrial physiological activity during hypoxia-induced acute brain injury could help serve as a potential therapeutic target to mitigate neurological damage.
急性缺氧引起的脑损伤与线粒体的生理活动有关。尽管线粒体是动态调节的，但我们对特定脑细胞类型对急性缺氧反应的全面理解仍不明确。肿瘤坏死因子受体相关蛋白 1（TRAP1）是一种基于线粒体的分子伴侣，在控制线粒体运动中发挥作用。在此，我们证明了急性缺氧在体内和体外脑损伤实验中显著改变了线粒体的形态和功能。基于汇总数据的孟德尔随机分析（SMR）揭示了与线粒体相关基因和缺氧损伤之间可能存在因果关系。推进蛋白质-蛋白质相互作用网络和分子对接进一步阐明了 TRAP1 与线粒体动力学之间的关联。此外，研究表明，TRAP1 敲低水平在原代海马神经元、星形胶质细胞和 BV-2 细胞中对关键线粒体动力学蛋白（DRP1、FIS1 和 MFN1/2）的表达产生了不同的影响，导致线粒体结构和功能发生变化。了解 TRAP1 在改变缺氧诱导的急性脑损伤期间线粒体生理活性中的作用可能有助于作为减轻神经损伤的潜在治疗靶点。
