School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, 210023, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, 210023, China.
Redox Biol. 2024 Jul;73:103196. doi: 10.1016/j.redox.2024.103196. Epub 2024 May 16.
Hippocampal neural stem/progenitor cells (NSPCs) are highly vulnerable to different stress stimuli, resulting in adult neurogenesis decline and eventual cognitive defects. Our previous study demonstrated that NOD-like receptor family pyrin domain-containing 6 (Nlrp6) highly expressed in NSPCs played a critical role in sustaining hippocampal neurogenesis to resist stress-induced depression, but the underlying mechnistms are still unclear. Here, we found that Nlrp6 depletion led to cognitive defects and hippocampal NSPC loss in mice. RNA-sequencing analysis of the primary NSPCs revealed that Nlrp6 deficiency altered gene expression profiles of mitochondrial energy generation and ferroptotic process. Upon siNlrp6 transfection, as well as corticosterone (CORT) exposure, downregulation of Nlrp6 suppressed retinoic acid-inducible gene I (RIG-1)/mitochondrial antiviral signaling proteins (MAVS)-mediated autophagy, but drove NSPC ferroptotic death. More interesting, short chain fatty acids (SCFAs) upregulated Nlrp6 expression and promoted RIG-1/MAVS-mediated mitophagy, preventing CORT-induced NSPC ferroptosis. Our study further demonstrates that Nlrp6 should be a sensor for RIG-1/MAVS-mediated mitophagy and play a critical role in maintain mitochondrial homeostasis of hippocampal NSPCs. These results suggests that Nlrp6 should be a potential drug target to combat neurodegenerative diseases relative with chronic stress.
海马神经干细胞/祖细胞（NSPCs）对不同的应激刺激高度敏感，导致成年神经发生下降和最终认知缺陷。我们之前的研究表明，在 NSPCs 中高度表达的 NOD 样受体家族 pyrin 结构域包含 6（Nlrp6）在维持海马神经发生以抵抗应激诱导的抑郁方面起着关键作用，但潜在的机制仍不清楚。在这里，我们发现 Nlrp6 耗竭导致小鼠认知缺陷和海马 NSPC 丧失。对原代 NSPCs 的 RNA 测序分析显示，Nlrp6 缺乏改变了线粒体能量产生和铁死亡过程的基因表达谱。在 siNlrp6 转染以及皮质酮（CORT）暴露后，Nlrp6 的下调抑制了视黄酸诱导基因 I（RIG-1）/线粒体抗病毒信号蛋白（MAVS）介导的自噬，但驱动了 NSPC 的铁死亡。更有趣的是，短链脂肪酸（SCFAs）上调了 Nlrp6 的表达并促进了 RIG-1/MAVS 介导的线粒体自噬，从而防止 CORT 诱导的 NSPC 铁死亡。我们的研究进一步表明，Nlrp6 应该是 RIG-1/MAVS 介导的线粒体自噬的传感器，并在维持海马 NSPCs 线粒体动态平衡中发挥关键作用。这些结果表明，Nlrp6 可能是对抗与慢性应激相关的神经退行性疾病的潜在药物靶点。
