Long-term cadmium exposure impairs cognitive function by activating lnc-Gm10532/m6A/FIS1 axis-mediated mitochondrial fission and dysfunction

被引:34
作者
Deng, Ping [1 ]
Zhang, Huadong [2 ]
Wang, Liting [3 ]
Jie, Sheng [1 ]
Zhao, Qi [2 ]
Chen, Fengqiong [2 ]
Yue, Yang [1 ]
Wang, Hui [1 ]
Tian, Li [1 ]
Xie, Jia [1 ]
Chen, Mengyan [1 ]
Luo, Yan [1 ]
Yu, Zhengping [1 ]
Pi, Huifeng [1 ]
Zhou, Zhou [4 ,5 ,6 ]
机构
[1] Third Mil Med Univ, Dept Occupat Hlth, Key Lab Electromagnet Radiat Protect, Minist Educ, Chongqing 400038, Peoples R China
[2] Chongqing Ctr Dis Control & Prevent, Chongqing 400042, Peoples R China
[3] Third Mil Med Univ, Biomed Anal Ctr, Chongqing 400038, Peoples R China
[4] Chongqing Univ, Ctr Neurointelligence, Sch Med, Chongqing 400030, Peoples R China
[5] Zhejiang Univ, Sch Publ Hlth, Dept Environm Med, Hangzhou 310058, Peoples R China
[6] Zhejiang Univ, Affiliated Hosp 1, Sch Med, Dept Emergency Med, Hangzhou 310058, Peoples R China
基金
中国国家自然科学基金;
关键词
Environmental heavy metal; Memory disorder; Long noncoding RNAs; Mitochondrial homeostasis; Epigeneticmodification; RNA; DYNAMICS; DRP1;
D O I
10.1016/j.scitotenv.2022.159950
中图分类号
X [环境科学、安全科学];
学科分类号
08 ; 0830 ;
摘要
Cadmium (Cd), a ubiquitous environmental contaminant, is deemed a possible aetiological cause of cognitive disor-ders 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 mu M for Neuro-2a cells or 0.5,1, and 1.5 mu M for hippocampal neurons) cadmium chlo-ride (CdCl2) for 72 h (h), and male mice (C57BL/6J, 8 weeks) were orally administered CdCl2 (0.6 mg/L, approxi-mately equal to 2.58 mu g/kgmiddotbw/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 spe-cies (ROS) production, altering mitochondrial membrane potential (bajim) 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 mu M 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.
引用
收藏
页数:15
相关论文
共 72 条
  • [1] A longitudinal study of rural Bangladeshi children with long-term arsenic and cadmium exposures and biomarkers of cardiometabolic diseases
    Akhtar, Evana
    Roy, Anjan Kumar
    Haq, Md Ahsanul
    von Ehrenstein, Ondine S.
    Ahmed, Sultan
    Vahter, Marie
    Ekstrom, Eva-Charlotte
    Kippler, Maria
    Wagatsuma, Yukiko
    Raqib, Rubhana
    [J]. ENVIRONMENTAL POLLUTION, 2021, 271
  • [2] Heavy Metals Exposure and Alzheimer's Disease and Related Dementias
    Bakulski, Kelly M.
    Seo, Young Ah
    Hickman, Ruby C.
    Brandt, Daniel
    Vadari, Harita S.
    Hu, Howard
    Park, Sung Kyun
    [J]. JOURNAL OF ALZHEIMERS DISEASE, 2020, 76 (04) : 1215 - 1242
  • [3] Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity
    Bertholet, A. M.
    Delerue, T.
    Millet, A. M.
    Moulis, M. F.
    David, C.
    Daloyau, M.
    Arnaune-Pelloquin, L.
    Davezac, N.
    Mils, V.
    Miguel, M. C.
    Rojo, M.
    Belenguer, P.
    [J]. NEUROBIOLOGY OF DISEASE, 2016, 90 : 3 - 19
  • [4] Cadmium-Induced Cytotoxicity: Effects on Mitochondrial Electron Transport Chain
    Branca, Jacopo Junio Valerio
    Pacini, Alessandra
    Gulisano, Massimo
    Taddei, Niccolo
    Fiorillo, Claudia
    Becatti, Matteo
    [J]. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2020, 8
  • [5] Cadmium-induced neurotoxicity: still much ado
    Branca, Jacopo Junio Valerio
    Morucci, Gabriele
    Pacini, Alessandra
    [J]. NEURAL REGENERATION RESEARCH, 2018, 13 (11) : 1879 - 1882
  • [6] LNCcation: lncRNA localization and function
    Bridges, Mary Catherine
    Daulagala, Amanda C.
    Kourtidis, Antonis
    [J]. JOURNAL OF CELL BIOLOGY, 2021, 220 (02)
  • [7] Disturbed mitochondrial dynamics and neurodegenerative disorders
    Burte, Florence
    Carelli, Valerio
    Chinnery, Patrick F.
    Yu-Wai-Man, Patrick
    [J]. NATURE REVIEWS NEUROLOGY, 2015, 11 (01) : 11 - 24
  • [8] Cadmium exposure causes mitochondrial fission and fusion disorder in the pig hypothalamus via the PI3K/AKT pathway
    Chen, Dan
    Yao, Yujie
    Shi, Xu
    Li, Xiaohang
    Cui, Wei
    Xu, Shiwen
    [J]. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY, 2022, 242
  • [9] LncRNA CASC11 Promotes Hepatocellular Carcinoma Progression via Upregulation of UBE2T in a m6A-Dependent Manner
    Chen, Fei
    Li, Meijun
    Wang, Liang
    [J]. FRONTIERS IN ONCOLOGY, 2021, 11
  • [10] Long noncoding RNA lnc-H2AFV-1 promotes cell growth by regulating aberrant m6A RNA modification in head and neck squamous cell carcinoma
    Chen, Xi
    Liu, Yunxia
    Sun, Dongyuan
    Sun, Rongqi
    Wang, Xiaoxiao
    Li, Minmin
    Song, Ning
    Ying, Jicheng
    Guo, Tao
    Jiang, Yingying
    [J]. CANCER SCIENCE, 2022, 113 (06) : 2071 - 2084