Journal Article

Polystyrene nanoplastic exposure induces excessive mitophagy by activating AMPK/ULK1 pathway in differentiated SH-SY5Y cells and dopaminergic neurons in vivo

Du, Jiaxin, Min, Weicui, Bai, Ruobing, Xian, Hongyi, Zhong, Yizhou, Fan, Bingchi, Ye, Rongyi, Yan, Xiliang, Huang, Zhenlie, Huang, Yuji, Zhang, Bingli, Li, Zhiming, Wang, Bo, Feng, Yu, Deng, Yanhong, Yang, Xingfen, Liang, Boxuan

2023

Overview

Background Microplastics and nanoplastics (MNPs) are emerging environmental contaminants detected in human samples, and have raised concerns regarding their potential risks to human health, particularly neurotoxicity. This study aimed to investigate the deleterious effects of polystyrene nanoplastics (PS-NPs, 50 nm) and understand their mechanisms in inducing Parkinson's disease (PD)-like neurodegeneration, along with exploring preventive strategies. Methods Following exposure to PS-NPs (0.5–500 μg/mL), we assessed cytotoxicity, mitochondrial integrity, ATP levels, and mitochondrial respiration in dopaminergic-differentiated SH-SY5Y cells. Molecular docking and dynamic simulations explored PS-NPs' interactions with mitochondrial complexes. We further probed mitophagy's pivotal role in PS-NP-induced mitochondrial damage and examined melatonin's ameliorative potential in vitro. We validated melatonin's intervention (intraperitoneal, 10 mg/kg/d) in C57BL/6 J mice exposed to 250 mg/kg/d of PS-NPs for 28 days. Results In our in vitro experiments, we observed PS-NP accumulation in cells, including mitochondria, leading to cell toxicity and reduced viability. Notably, antioxidant treatment failed to fully rescue viability, suggesting reactive oxygen species (ROS)-independent cytotoxicity. PS-NPs caused significant mitochondrial damage, characterized by altered morphology, reduced mitochondrial membrane potential, and decreased ATP production. Subsequent investigations pointed to PS-NP-induced disruption of mitochondrial respiration, potentially through interference with complex I (CI), a concept supported by molecular docking studies highlighting the influence of PS-NPs on CI. Rescue experiments using an AMPK pathway inhibitor (compound C) and an autophagy inhibitor (3-methyladenine) revealed that excessive mitophagy was induced through AMPK/ULK1 pathway activation, worsening mitochondrial damage and subsequent cell death in differentiated SH-SY5Y cells. Notably, we identified melatonin as a potential protective agent, capable of alleviating PS-NP-induced mitochondrial dysfunction. Lastly, our in vivo experiments demonstrated that melatonin could mitigate dopaminergic neuron loss and motor impairments by restoring mitophagy regulation in mice. Conclusions Our study demonstrated that PS-NPs disrupt mitochondrial function by affecting CI, leading to excessive mitophagy through the AMPK/ULK1 pathway, causing dopaminergic neuron death. Melatonin can counteract PS-NP-induced mitochondrial dysfunction and motor impairments by regulating mitochondrial autophagy. These findings offer novel insights into the MNP-induced PD-like neurodegenerative mechanisms, and highlight melatonin's protective potential in mitigating the MNP’s environmental risk.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenosine Triphosphate - metabolism / AMP-Activated Protein Kinases - metabolism / AMP-Activated Protein Kinases - pharmacology / Animals / Antioxidants / Autophagy / Autophagy (Cytology) / Autophagy-Related Protein-1 Homolog - metabolism / Biocompatibility / Biomedical and Life Sciences / Biomedicine / Brain research / Cell death / Cell differentiation / Complex I / Contaminants / Cytotoxicity / Damage / Degeneration / Dopamine receptors / Dopaminergic mechanisms / Dopaminergic Neurons - metabolism / Electron transport chain / Energy / Environmental Health / Environmental risk / Exposure / Fluid dynamics / Health aspects / Homeostasis / Humans / Inhibitors / Intracellular Signaling Peptides and Proteins - metabolism / Intracellular Signaling Peptides and Proteins - pharmacology / Investigations / Medical research / Medicine, Experimental / Melatonin / Melatonin - metabolism / Melatonin - pharmacology / Membrane potential / Metabolic disorders / Mice / Mice, Inbred C57BL / Microplastics / Microplastics and nanoplastics / Mitochondria / Mitochondrial DNA / Mitochondrial dysfunction / Mitophagy / Molecular docking / Molecular Docking Simulation / Morphology / Movement disorders / Nanotechnology / Nervous system / Neuroblastoma - metabolism / Neurodegeneration / Neurodegenerative diseases / Neurons / Neurotoxicity / Parkinson's disease / Pharmacology/Toxicology / Plastic pollution / Plastics / Pneumology/Respiratory System / Polyethylene / Polystyrene / Polystyrene resins / Polystyrenes - metabolism / Protein kinases / Public Health / Reactive oxygen species / Reactive Oxygen Species - metabolism / Respiration / Scanning electron microscopy / Toxicity