Tang Yanling, Zhang Jingjing, Hu Zeyu, Xu Wanjing, Xu Panpan, Ma Yue, Xing Hengrui, Niu Qiang
Department of Preventive Medicine, School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; Key Laboratory of Preventive Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (First Affiliated Hospital, School of Medicine, Shihezi University), People's Republic of China.
Department of Preventive Medicine, School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; Key Laboratory of Preventive Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi, Xinjiang, People's Republic of China; NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases (First Affiliated Hospital, School of Medicine, Shihezi University), People's Republic of China.
Ecotoxicol Environ Saf. 2023 Apr 15;255:114772. doi: 10.1016/j.ecoenv.2023.114772. Epub 2023 Mar 14.
Chronic fluoride exposure can cause developmental neurotoxicity, however the precise mechanisms remain unclear. To explore the mechanism of mitophagy in fluoride-induced developmental neurotoxicity, specifically focusing on PRKAA1 in regulating the PINK1/Parkin pathway, we established a Sprage Dawley rat model with continuous sodium fluoride (NaF) exposure and an NaF-treated SH-SY5Y cell model. We found that NaF exposure increased the levels of LC3-Ⅱ and p62, impaired autophagic degradation, and subsequently blocked autophagic flux. Additionally, NaF exposure increased the expression of PINK1, Parkin, TOMM-20, and Cyt C and cleaved PARP in vivo and in vitro, indicating NaF promotes mitophagy and neuronal apoptosis. Meanwhile, phosphoproteomics and western blot analysis showed that NaF treatment enhanced PRKAA1 phosphorylation. Remarkably, the application of both 3-methyladenosine (3-MA; autophagy inhibitor) and dorsomorphin (DM; AMPK inhibitor) suppressed NaF-induced neuronal apoptosis by restoring aberrant mitophagy. In addition, 3-MA attenuated an increase in p62 protein levels and NaF-induced autophagic degradation. Collectively, our findings indicated that NaF causes aberrant mitophagy via PRKAA1 in a PINK1/Parkin-dependent manner, which triggers neuronal apoptosis. Thus, regulating PRKAA1-activated PINK1/Parkin-dependent mitophagy may be a potential treatment for NaF-induced developmental neurotoxicity.
长期接触氟化物会导致发育性神经毒性，但其确切机制尚不清楚。为了探究线粒体自噬在氟化物诱导的发育性神经毒性中的作用机制，特别是聚焦于PRKAA1对PINK1/Parkin通路的调控，我们建立了持续暴露于氟化钠（NaF）的Sprage Dawley大鼠模型以及NaF处理的SH-SY5Y细胞模型。我们发现，暴露于NaF会增加LC3-Ⅱ和p62的水平，损害自噬降解，随后阻断自噬流。此外，NaF暴露会增加PINK1、Parkin、TOMM-20和Cyt C的表达，并在体内和体外切割PARP，表明NaF促进线粒体自噬和神经元凋亡。同时，磷酸化蛋白质组学和蛋白质免疫印迹分析表明，NaF处理增强了PRKAA1的磷酸化。值得注意的是，应用3-甲基腺嘌呤（3-MA；自噬抑制剂）和 dorsomorphin（DM；AMPK抑制剂）均通过恢复异常的线粒体自噬抑制了NaF诱导的神经元凋亡。此外，3-MA减弱了p62蛋白水平的升高以及NaF诱导的自噬降解。总的来说，我们的研究结果表明，NaF通过PRKAA1以PINK1/Parkin依赖的方式导致异常的线粒体自噬，进而引发神经元凋亡。因此，调节PRKAA1激活的PINK1/Parkin依赖的线粒体自噬可能是治疗NaF诱导的发育性神经毒性的一种潜在方法。
