Particulate Matter-Induced Neurotoxicity: Unveiling the Role of NOX4-Mediated ROS Production and Mitochondrial Dysfunction in Neuronal Apoptosis

Author:

Kim Ji-Hee1ORCID,Hwang Kyu-Hee234,Kim Seong-Heon5ORCID,Kim Hi-Ju6,Kim Jung-Min7,Lee Mi-Young78ORCID,Cha Seung-Kuy234,Lee Jinhee6ORCID

Affiliation:

1. Department of Occupational Therapy, Soonchunhyang University, Asan-si 31538, Republic of Korea

2. Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea

3. Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea

4. Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea

5. Department of Environmental and Energy Engineering, Yonsei University, Wonju 26493, Republic of Korea

6. Department of Psychiatry, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea

7. Department of Medical Science, Soonchunhyang University, Asan-si 31538, Republic of Korea

8. Department of Medical Biotechnology, Soonchunhyang University, Asan-si 31538, Republic of Korea

Abstract

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.

Funder

National Research Foundation of Korea

Ministry of Education

Publisher

MDPI AG

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