Department of Occupational Therapy, Soonchunhyang University, Asan-si 31538, Republic of Korea.
Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea.
Int J Mol Sci. 2024 Jun 1;25(11):6116. doi: 10.3390/ijms25116116.
Urban air pollution, a significant environmental hazard, is linked to adverse health outcomes and increased mortality across various diseases. This study investigates the neurotoxic effects of particulate matter (PM), specifically PM2.5 and PM10, by examining their role in inducing oxidative stress and subsequent neuronal cell death. We highlight the novel finding that PM increases mitochondrial ROS production via stimulating NOX4 activity, not through its expression level in Neuro-2A cells. Additionally, PMs provoke ROS production via increasing the expression and activity of NOX2 in SH-SY5Y human neuroblastoma cells, implying differential regulation of NOX proteins. This increase in mitochondrial ROS triggers the opening of the mitochondrial permeability transition pore (mPTP), leading to apoptosis through key mediators, including caspase3, BAX, and Bcl2. Notably, the voltage-dependent anion-selective channel 1 (VDAC1) increases at 1 µg/mL of PM2.5, while PM10 triggers an increase from 10 µg/mL. At the same concentration (100 µg/mL), PM2.5 causes 1.4 times higher ROS production and 2.4 times higher NOX4 activity than PM10. The cytotoxic effects induced by PMs were alleviated by NOX inhibitors GKT137831 and Apocynin. In SH-SY5Y cells, both PM types increase ROS and NOX2 levels, leading to cell death, which Apocynin rescues. Variability in NADPH oxidase sources underscores the complexity of PM-induced neurotoxicity. Our findings highlight NOX4-driven ROS and mitochondrial dysfunction, suggesting a potential therapeutic approach for mitigating PM-induced neurotoxicity.
城市空气污染是一种严重的环境危害，它与各种疾病的不良健康后果和死亡率增加有关。本研究通过研究颗粒物（PM），特别是 PM2.5 和 PM10，来探讨其诱导氧化应激和随后神经元细胞死亡的神经毒性作用。我们强调了一个新的发现，即 PM 通过刺激 NOX4 活性而不是通过其在 Neuro-2A 细胞中的表达水平来增加线粒体 ROS 的产生。此外，PM 通过增加 SH-SY5Y 人神经母细胞瘤细胞中 NOX2 的表达和活性来引起 ROS 的产生，这表明 NOX 蛋白的调节存在差异。这种线粒体 ROS 的增加触发了线粒体通透性转换孔（mPTP）的开放，通过关键介质，包括 caspase3、BAX 和 Bcl2，导致细胞凋亡。值得注意的是，在 1 µg/mL 的 PM2.5 下，电压依赖性阴离子选择通道 1（VDAC1）增加，而 PM10 则从 10 µg/mL 开始增加。在相同浓度（100 µg/mL）下，PM2.5 引起的 ROS 产生比 PM10 高 1.4 倍，NOX4 活性高 2.4 倍。NOX 抑制剂 GKT137831 和 Apocynin 减轻了 PM 引起的细胞毒性作用。在 SH-SY5Y 细胞中，两种 PM 类型均增加了 ROS 和 NOX2 水平，导致细胞死亡，而 Apocynin 可挽救这种死亡。NADPH 氧化酶来源的可变性突出了 PM 诱导的神经毒性的复杂性。我们的研究结果强调了 NOX4 驱动的 ROS 和线粒体功能障碍，这表明了一种减轻 PM 诱导的神经毒性的潜在治疗方法。
