Department of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China; Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, China.
Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, the Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu 610000, China; Department of Pulmonary and Critical Care Medicine, Chengdu Third People's Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu 610000, China.
Ecotoxicol Environ Saf. 2024 Jun 1;277:116314. doi: 10.1016/j.ecoenv.2024.116314. Epub 2024 Apr 19.
Fine particulate matter (PM2.5) has been extensively implicated in the pathogenesis of neurodevelopmental disorders, but the underlying mechanism remains unclear. Recent studies have revealed that PM2.5 plays a role in regulating iron metabolism and redox homeostasis in the brain, which is closely associated with ferroptosis. In this study, the role and underlying mechanism of ferroptosis in PM2.5-induced neurotoxicity were investigated in mice, primary hippocampal neurons, and HT22 cells. Our findings demonstrated that exposure to PM2.5 could induce abnormal behaviors, neuroinflammation, and neuronal loss in the hippocampus of mice. These effects may be attributed to ferroptosis induced by PM2.5 exposure in hippocampal neurons. RNA-seq analysis revealed that the upregulation of iron metabolism-related protein Heme Oxygenase 1 (HO-1) and the activation of mitophagy might play key roles in PM2.5-induced ferroptosis in HT22 cells. Subsequent in vitro experiments showed that PM2.5 exposure significantly upregulated HO-1 in primary hippocampal neurons and HT22 cells. Moreover, PM2.5 exposure activated mitophagy in HT22 cells, leading to the loss of mitochondrial membrane potential, alterations in the expression of autophagy-related proteins LC3, P62, and mTOR, as well as an increase in mitophagy-related protein PINK1 and PARKIN. As a heme-degradation enzyme, the upregulation of HO-1 promotes the release of excess iron, genetically inhibiting the upregulation of HO-1 in HT22 cells could prevent both PM2.5-induced mitophagy and ferroptosis. Furthermore, pharmacological inhibition of mitophagy in HT22 cells reduced levels of ferrous ions and lipid peroxides, thereby preventing ferroptosis. Collectively, this study demonstrates that HO-1 mediates PM2.5-induced mitophagy-dependent ferroptosis in hippocampal neurons, and inhibiting mitophagy or ferroptosis may be a key therapeutic target to ameliorate neurotoxicity following PM2.5 exposure.
细颗粒物（PM2.5）已被广泛认为与神经发育障碍的发病机制有关，但潜在机制尚不清楚。最近的研究表明，PM2.5 在调节大脑中的铁代谢和氧化还原平衡方面发挥作用，这与铁死亡密切相关。在这项研究中，研究了铁死亡在 PM2.5 诱导的神经毒性中的作用和潜在机制，在小鼠、原代海马神经元和 HT22 细胞中进行了研究。我们的研究结果表明，暴露于 PM2.5 可诱导小鼠海马区异常行为、神经炎症和神经元丢失。这些影响可能归因于 PM2.5 暴露诱导海马神经元发生铁死亡。RNA-seq 分析表明，铁代谢相关蛋白血红素加氧酶 1（HO-1）的上调和线粒体自噬的激活可能在 PM2.5 诱导的 HT22 细胞铁死亡中发挥关键作用。随后的体外实验表明，PM2.5 暴露可显著上调原代海马神经元和 HT22 细胞中的 HO-1。此外，PM2.5 暴露激活 HT22 细胞中的线粒体自噬，导致线粒体膜电位丧失、自噬相关蛋白 LC3、P62 和 mTOR 的表达改变，以及自噬相关蛋白 PINK1 和 PARKIN 的增加。作为血红素降解酶，HO-1 的上调促进过量铁的释放，遗传抑制 HT22 细胞中 HO-1 的上调可防止 PM2.5 诱导的线粒体自噬和铁死亡。此外，HT22 细胞中线粒体自噬的药理学抑制降低了亚铁离子和脂质过氧化物的水平，从而防止了铁死亡。综上所述，本研究表明 HO-1 介导了 PM2.5 诱导的海马神经元中依赖于线粒体自噬的铁死亡，抑制线粒体自噬或铁死亡可能是改善 PM2.5 暴露后神经毒性的关键治疗靶点。
