Su Zhongqiang, Shu Hui, Huang Xingting, Ding Liuyan, Liang Fengchu, Xu Zongtang, Zhu Ziting, Chen Minshan, Wang Xiaobei, Li Guihua, Xia Huan, Cao Qiannan, Zhang Wenlong, Xu Pingyi, Yang Xinling
Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Ürümqi, 830054, Xinjiang, China.
Xinjiang Key Laboratory of Neurological Disease Research, Ürümqi, 830054, Xinjiang, China.
Cell Mol Life Sci. 2025 Sep 6;82(1):337. doi: 10.1007/s00018-025-05873-9.
Microglial activation-induced neuroinflammation and impaired neuronal mitophagy are recognized as pivotal pathogeneses in Parkinson's disease (PD). However, the role of microglial mitophagy in microglial activation during PD development remains unclear, and therapeutic interventions targeting this interaction are lacking. Rhapontigenin (Rhap), a stilbenoid enriched in Vitis vinifera, exhibits dual anti-neuroinflammatory and mitophagy-enhancing properties, but its therapeutic potential and mechanisms in PD are unexplored. This study aimed to investigate the therapeutic efficacy of Rhap on neurodegeneration in a PD model and explore its underlying mechanism. Here, we showed that Rhap administration significantly ameliorated motor deficits, dopaminergic neuron loss, and neuroinflammation in MPTP-induced PD mice. Mechanistically, Rhap suppressed neuroinflammation by inhibiting the cGAS-STING-NF-κB signaling axis in both PD model mice and MPP⁺-induced BV2 microglia. Crucially, its anti-inflammatory effects depend on the PINK1-mediated enhancement of microglial mitophagy to control cytosolic mtDNA leakage. Specifically, Rhap bound to PINK1 strengthened the PINK1-DRP1 interaction, promoted mitochondrial fission in damaged organelles, and enhanced mitophagy clearance. This mitophagy activation prevents cytosolic leakage of mitochondrial DNA (mtDNA), thereby attenuating mtDNA-cGAS-STING-NF-κB-derived neuroinflammation and subsequent neurodegeneration in PD. PINK1 deficiency in BV2 microglia abolished Rhap's ability to suppress mtDNA-cGAS-STING-NF-κB activation and enhance mitophagy. Overall, our study reveals a previously unrecognized mechanism by which Rhap ameliorates PD-associated neurodegeneration through dual modulation of PINK1/DRP1-dependent microglial mitophagy and the mtDNA-cGAS-STING-NF-κB neuroinflammatory axis, suggesting a potential therapeutic strategy for PD and related neurodegenerative disorders.
小胶质细胞激活诱导的神经炎症和神经元线粒体自噬受损被认为是帕金森病（PD）的关键发病机制。然而，小胶质细胞线粒体自噬在PD发展过程中小胶质细胞激活中的作用仍不清楚，且缺乏针对这种相互作用的治疗干预措施。白藜芦醇（Rhap）是一种富含于葡萄中的芪类化合物，具有双重抗神经炎症和增强线粒体自噬的特性，但其在PD中的治疗潜力和机制尚未得到探索。本研究旨在探讨Rhap对PD模型中神经退行性变的治疗效果，并探索其潜在机制。在此，我们表明给予Rhap可显著改善MPTP诱导的PD小鼠的运动功能障碍、多巴胺能神经元丢失和神经炎症。机制上，Rhap通过抑制PD模型小鼠和MPP⁺诱导的BV2小胶质细胞中的cGAS-STING-NF-κB信号轴来抑制神经炎症。至关重要的是，其抗炎作用依赖于PINK1介导的小胶质细胞线粒体自噬增强，以控制细胞质中线粒体DNA泄漏。具体而言，与PINK1结合的Rhap加强了PINK1-DRP1相互作用，促进受损细胞器中的线粒体分裂，并增强线粒体自噬清除。这种线粒体自噬激活可防止线粒体DNA（mtDNA）的细胞质泄漏，从而减轻PD中mtDNA-cGAS-STING-NF-κB衍生的神经炎症和随后的神经退行性变B。BV2小胶质细胞中PINK1缺乏消除了Rhap抑制mtDNA-cGAS-STING-NF-κB激活和增强线粒体自噬的能力。总体而言，我们的研究揭示了一种先前未被认识的机制，即Rhap通过对PINK1/DRP1依赖性小胶质细胞线粒体自噬和mtDNA-cGAS-STING-NF-κB神经炎症轴的双重调节来改善PD相关的神经退行性变，为PD和相关神经退行性疾病提出了一种潜在的治疗策略。
