Zeng Qing, Huang Bei-Xu, Liu Chang, Liang Nen, Yu Jian, Liao Song-Jie
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology , Guangzhou, 510080, China.
Mol Neurobiol. 2025 Jul 22. doi: 10.1007/s12035-025-05202-y.
Neuropathic pain (NP) is a common chronic pain that lacks durable, mechanism-based therapies, making it a global health concern. Mitochondrial protection is essential to alleviate oxidative stress and maintain normal energy metabolism, playing a critical role in the treatment of NP. Mammalian ste20-like kinase 2 (Mst2) is a key protein in the Hippo pathway and plays a pivotal role in regulating mitochondrial function. Sirt1 mediates autophagy and BNIP3-related mitophagy, and is modulated by the phosphorylation of the Hippo pathway. Utilizing a sciatic nerve constriction injury (CCI) model on male rats to simulate traumatic NP, we further administered Mst2-siRNA to the injured sciatic nerve. Behavioral tests revealed that Mst2 knockdown significantly alleviated CCI-induced NP. Morphological analysis and western blot showed that the observed effects of Mst2 knockdown were attributed to the promotion of autophagy and the activation of BNIP3-mediated mitophagy. These processes contributed to the protection of mitochondria, myelin and axons within the sciatic nerve. In vitro studies in Schwann cell line and SH‑SY5Y‑derived neuroblastoma cells confirmed that Mst2 knockdown promotes autophagic flux and induces BNIP3‑mediated mitophagy, safeguarding mitochondrial function. Mechanistically, our study further showed that Mst2 downregulation reduces Sirt1 phosphorylation and elevates FOXO3‑driven BNIP3 transcription, establishing the significant role of Mst2 in Sirt1/FOXO3/BNIP3 regulation. These findings position Mst2 as a critical modulator in nerve injury-induced NP, highlighting autophagy and mitophagy regulation as potential targets for novel NP therapies.
神经性疼痛（NP）是一种常见的慢性疼痛，缺乏持久的、基于机制的治疗方法，这使其成为一个全球健康问题。线粒体保护对于减轻氧化应激和维持正常能量代谢至关重要，在NP的治疗中起着关键作用。哺乳动物类Ste20样激酶2（Mst2）是Hippo信号通路中的关键蛋白，在调节线粒体功能中起关键作用。Sirt1介导自噬和BNIP3相关的线粒体自噬，并受Hippo信号通路磷酸化的调节。利用雄性大鼠坐骨神经缩窄损伤（CCI）模型模拟创伤性NP，我们进一步将Mst2-siRNA注射到损伤的坐骨神经中。行为测试表明，敲低Mst2可显著减轻CCI诱导的NP。形态学分析和蛋白质印迹显示，敲低Mst2的观察到的效果归因于自噬的促进和BNIP3介导的线粒体自噬的激活。这些过程有助于保护坐骨神经内的线粒体、髓鞘和轴突。在雪旺细胞系和SH-SY5Y衍生的神经母细胞瘤细胞中的体外研究证实，敲低Mst2可促进自噬通量并诱导BNIP3介导的线粒体自噬，保护线粒体功能。从机制上讲，我们的研究进一步表明，Mst2下调会降低Sirt1磷酸化并提高FOXO3驱动的BNIP3转录，确立了Mst2在Sirt1/FOXO3/BNIP3调节中的重要作用。这些发现将Mst2定位为神经损伤诱导的NP中的关键调节因子，突出了自噬和线粒体自噬调节作为新型NP治疗潜在靶点的地位。
