Ping Deng , Huadong Zhang , Liting Wang , Sheng Jie , Qi Zhao , Fengqiong Chen , Yang Yue , Hui Wang , Li Tian , Jia Xie , Mengyan Chen , Yan Luo , Zhengping Yu , Huifeng Pi , Zhou Zhou
{"title":"长期镉暴露通过激活lnc-Gm10532/m6A/FIS1轴介导的线粒体分裂和功能障碍损害认知功能","authors":"Ping Deng , Huadong Zhang , Liting Wang , Sheng Jie , Qi Zhao , Fengqiong Chen , Yang Yue , Hui Wang , Li Tian , Jia Xie , Mengyan Chen , Yan Luo , Zhengping Yu , Huifeng Pi , Zhou Zhou","doi":"10.1016/j.scitotenv.2022.159950","DOIUrl":null,"url":null,"abstract":"<div><p>Cadmium (Cd), a ubiquitous environmental contaminant, is deemed a possible aetiological cause of cognitive disorders in humans. Nevertheless, the exact mechanism by which chronic exposure to Cd causes neurotoxicity is not fully understood. In this study, mouse neuroblastoma cells (Neuro-2a cells) and primary hippocampal neurons were exposed to low-dose (1, 2, and 4 μM for Neuro-2a cells or 0.5, 1, and 1.5 μM for hippocampal neurons) cadmium chloride (CdCl<sub>2</sub>) for 72 h (h), and male mice (C57BL/6J, 8 weeks) were orally administered CdCl<sub>2</sub> (0.6 mg/L, approximately equal to 2.58 μg/kg·bw/d) for 6 months to investigate the effects and mechanism of chronic Cd-induced neurotoxicity. Here, chronic exposure to Cd impaired mitochondrial function by promoting excess reactive oxygen species (ROS) production, altering mitochondrial membrane potential (Δψm) and reducing adenosine triphosphate (ATP) content, contributing to neuronal cell death. Specifically, microarray analysis revealed that the long noncoding RNA <em>Gm10532</em> (lnc-<em>Gm10532</em>) was most highly expressed in Neuro-2a cells exposed to 4 μM CdCl<sub>2</sub> for 72 h compared with controls, and inhibition of lnc-Gm10532 significantly antagonized CdCl<sub>2</sub>-induced mitochondrial dysfunction and neurotoxicity. Mechanistically, lnc-<em>Gm10532</em> increased Fission 1 (FIS1) expression and mitochondrial fission by recruiting the m6A writer methyltransferase-like 14 (METTL14) and enhancing m6A modification of <em>Fis1</em> mRNA. Moreover, lnc-<em>Gm10532</em> was also required for chronic Cd-induced mitochondrial dysfunction and memory deficits in a rodent model. Therefore, data of this study reveal a new epigenetic mechanism of chronic Cd neurotoxicity.</p></div>","PeriodicalId":422,"journal":{"name":"Science of the Total Environment","volume":null,"pages":null},"PeriodicalIF":8.2000,"publicationDate":"2023-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"7","resultStr":"{\"title\":\"Long-term cadmium exposure impairs cognitive function by activating lnc-Gm10532/m6A/FIS1 axis-mediated mitochondrial fission and dysfunction\",\"authors\":\"Ping Deng , Huadong Zhang , Liting Wang , Sheng Jie , Qi Zhao , Fengqiong Chen , Yang Yue , Hui Wang , Li Tian , Jia Xie , Mengyan Chen , Yan Luo , Zhengping Yu , Huifeng Pi , Zhou Zhou\",\"doi\":\"10.1016/j.scitotenv.2022.159950\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Cadmium (Cd), a ubiquitous environmental contaminant, is deemed a possible aetiological cause of cognitive disorders in humans. Nevertheless, the exact mechanism by which chronic exposure to Cd causes neurotoxicity is not fully understood. In this study, mouse neuroblastoma cells (Neuro-2a cells) and primary hippocampal neurons were exposed to low-dose (1, 2, and 4 μM for Neuro-2a cells or 0.5, 1, and 1.5 μM for hippocampal neurons) cadmium chloride (CdCl<sub>2</sub>) for 72 h (h), and male mice (C57BL/6J, 8 weeks) were orally administered CdCl<sub>2</sub> (0.6 mg/L, approximately equal to 2.58 μg/kg·bw/d) for 6 months to investigate the effects and mechanism of chronic Cd-induced neurotoxicity. Here, chronic exposure to Cd impaired mitochondrial function by promoting excess reactive oxygen species (ROS) production, altering mitochondrial membrane potential (Δψm) and reducing adenosine triphosphate (ATP) content, contributing to neuronal cell death. Specifically, microarray analysis revealed that the long noncoding RNA <em>Gm10532</em> (lnc-<em>Gm10532</em>) was most highly expressed in Neuro-2a cells exposed to 4 μM CdCl<sub>2</sub> for 72 h compared with controls, and inhibition of lnc-Gm10532 significantly antagonized CdCl<sub>2</sub>-induced mitochondrial dysfunction and neurotoxicity. Mechanistically, lnc-<em>Gm10532</em> increased Fission 1 (FIS1) expression and mitochondrial fission by recruiting the m6A writer methyltransferase-like 14 (METTL14) and enhancing m6A modification of <em>Fis1</em> mRNA. Moreover, lnc-<em>Gm10532</em> was also required for chronic Cd-induced mitochondrial dysfunction and memory deficits in a rodent model. Therefore, data of this study reveal a new epigenetic mechanism of chronic Cd neurotoxicity.</p></div>\",\"PeriodicalId\":422,\"journal\":{\"name\":\"Science of the Total Environment\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2023-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"7\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science of the Total Environment\",\"FirstCategoryId\":\"93\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0048969722070504\",\"RegionNum\":1,\"RegionCategory\":\"环境科学与生态学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENVIRONMENTAL SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science of the Total Environment","FirstCategoryId":"93","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0048969722070504","RegionNum":1,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENVIRONMENTAL SCIENCES","Score":null,"Total":0}
Long-term cadmium exposure impairs cognitive function by activating lnc-Gm10532/m6A/FIS1 axis-mediated mitochondrial fission and dysfunction
Cadmium (Cd), a ubiquitous environmental contaminant, is deemed a possible aetiological cause of cognitive disorders in humans. Nevertheless, the exact mechanism by which chronic exposure to Cd causes neurotoxicity is not fully understood. In this study, mouse neuroblastoma cells (Neuro-2a cells) and primary hippocampal neurons were exposed to low-dose (1, 2, and 4 μM for Neuro-2a cells or 0.5, 1, and 1.5 μM for hippocampal neurons) cadmium chloride (CdCl2) for 72 h (h), and male mice (C57BL/6J, 8 weeks) were orally administered CdCl2 (0.6 mg/L, approximately equal to 2.58 μg/kg·bw/d) for 6 months to investigate the effects and mechanism of chronic Cd-induced neurotoxicity. Here, chronic exposure to Cd impaired mitochondrial function by promoting excess reactive oxygen species (ROS) production, altering mitochondrial membrane potential (Δψm) and reducing adenosine triphosphate (ATP) content, contributing to neuronal cell death. Specifically, microarray analysis revealed that the long noncoding RNA Gm10532 (lnc-Gm10532) was most highly expressed in Neuro-2a cells exposed to 4 μM CdCl2 for 72 h compared with controls, and inhibition of lnc-Gm10532 significantly antagonized CdCl2-induced mitochondrial dysfunction and neurotoxicity. Mechanistically, lnc-Gm10532 increased Fission 1 (FIS1) expression and mitochondrial fission by recruiting the m6A writer methyltransferase-like 14 (METTL14) and enhancing m6A modification of Fis1 mRNA. Moreover, lnc-Gm10532 was also required for chronic Cd-induced mitochondrial dysfunction and memory deficits in a rodent model. Therefore, data of this study reveal a new epigenetic mechanism of chronic Cd neurotoxicity.
期刊介绍:
The Science of the Total Environment is an international journal dedicated to scientific research on the environment and its interaction with humanity. It covers a wide range of disciplines and seeks to publish innovative, hypothesis-driven, and impactful research that explores the entire environment, including the atmosphere, lithosphere, hydrosphere, biosphere, and anthroposphere.
The journal's updated Aims & Scope emphasizes the importance of interdisciplinary environmental research with broad impact. Priority is given to studies that advance fundamental understanding and explore the interconnectedness of multiple environmental spheres. Field studies are preferred, while laboratory experiments must demonstrate significant methodological advancements or mechanistic insights with direct relevance to the environment.