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

IF 7.2 1区 医学 Q1 TOXICOLOGY
Yuji Huang, Boxuan Liang, Zhiming Li, Yizhou Zhong, Bo Wang, Bingli Zhang, Jiaxin Du, Rongyi Ye, Hongyi Xian, Weicui Min, Xiliang Yan, Yanhong Deng, Yu Feng, Ruobing Bai, Bingchi Fan, Xingfen Yang, Zhenlie Huang
{"title":"Polystyrene nanoplastic exposure induces excessive mitophagy by activating AMPK/ULK1 pathway in differentiated SH-SY5Y cells and dopaminergic neurons in vivo.","authors":"Yuji Huang, Boxuan Liang, Zhiming Li, Yizhou Zhong, Bo Wang, Bingli Zhang, Jiaxin Du, Rongyi Ye, Hongyi Xian, Weicui Min, Xiliang Yan, Yanhong Deng, Yu Feng, Ruobing Bai, Bingchi Fan, Xingfen Yang, Zhenlie Huang","doi":"10.1186/s12989-023-00556-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":19847,"journal":{"name":"Particle and Fibre Toxicology","volume":"20 1","pages":"44"},"PeriodicalIF":7.2000,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664492/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Particle and Fibre Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12989-023-00556-4","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"TOXICOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

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.

在体内,聚苯乙烯纳米塑料暴露通过激活分化的SH-SY5Y细胞和多巴胺能神经元的AMPK/ULK1通路诱导过度的线粒体自噬。
背景:微塑料和纳米塑料(MNPs)是在人体样本中检测到的新兴环境污染物,它们对人类健康的潜在风险,特别是神经毒性,引起了人们的关注。本研究旨在探讨聚苯乙烯纳米塑料(PS-NPs, 50 nm)的有害作用,了解其诱导帕金森病(PD)样神经变性的机制,并探讨预防策略。方法:暴露于PS-NPs (0.5-500 μg/mL)后,我们评估了多巴胺能分化的SH-SY5Y细胞的细胞毒性、线粒体完整性、ATP水平和线粒体呼吸。分子对接和动态模拟研究了PS-NPs与线粒体复合物的相互作用。我们进一步探讨了线粒体自噬在ps - np诱导的线粒体损伤中的关键作用,并在体外检测了褪黑素的改善潜力。我们验证了褪黑素对暴露于250 mg/kg/d PS-NPs 28天的C57BL/6 J小鼠的干预作用(腹腔注射,10 mg/kg/d)。结果:在体外实验中,我们观察到PS-NP在细胞(包括线粒体)中积累,导致细胞毒性和活力降低。值得注意的是,抗氧化处理未能完全恢复细胞活力,提示不依赖活性氧(ROS)的细胞毒性。PS-NPs引起明显的线粒体损伤,表现为形态改变、线粒体膜电位降低和ATP生成减少。随后的研究指出,ps - np可能通过干扰复合体I (CI)诱导线粒体呼吸中断,这一概念得到了分子对接研究的支持,这些研究强调了ps - np对CI的影响。利用AMPK通路抑制剂(化合物C)和自噬抑制剂(3-甲基腺苷)进行的救援实验显示,在分化的SH-SY5Y细胞中,AMPK/ULK1通路的激活诱导了过度的线粒体自噬,加剧了线粒体损伤和随后的细胞死亡。值得注意的是,我们发现褪黑激素是一种潜在的保护剂,能够减轻ps - np诱导的线粒体功能障碍。最后,我们的体内实验表明,褪黑激素可以通过恢复小鼠的有丝分裂调节来减轻多巴胺能神经元的丧失和运动损伤。结论:我们的研究表明,PS-NPs通过影响CI破坏线粒体功能,通过AMPK/ULK1通路导致线粒体自噬过度,导致多巴胺能神经元死亡。褪黑素可以通过调节线粒体自噬来对抗ps - np诱导的线粒体功能障碍和运动障碍。这些发现为MNP诱导的pd样神经退行性机制提供了新的见解,并强调了褪黑素在减轻MNP环境风险方面的保护潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
15.90
自引率
4.00%
发文量
69
审稿时长
6 months
期刊介绍: Particle and Fibre Toxicology is an online journal that is open access and peer-reviewed. It covers a range of disciplines such as material science, biomaterials, and nanomedicine, focusing on the toxicological effects of particles and fibres. The journal serves as a platform for scientific debate and communication among toxicologists and scientists from different fields who work with particle and fibre materials. The main objective of the journal is to deepen our understanding of the physico-chemical properties of particles, their potential for human exposure, and the resulting biological effects. It also addresses regulatory issues related to particle exposure in workplaces and the general environment. Moreover, the journal recognizes that there are various situations where particles can pose a toxicological threat, such as the use of old materials in new applications or the introduction of new materials altogether. By encompassing all these disciplines, Particle and Fibre Toxicology provides a comprehensive source for research in this field.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信