title: Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria.
abstract: Cadmium (Cd) is a persistent environmental toxin and occupational pollutant that is considered to be a potential risk factor in the development of neurodegenerative diseases. Abnormal mitochondrial dynamics are increasingly implicated in mitochondrial damage in various neurological pathologies. The aim of this study was to investigate whether the disturbance of mitochondrial dynamics contributed to Cd-induced neurotoxicity and whether melatonin has any neuroprotective properties. After cortical neurons were exposed to 10 μM cadmium chloride (CdCl2 ) for various periods (0, 3, 6, 12, and 24 hr), the morphology of their mitochondria significantly changed from the normal tubular networks into punctuated structures within 3 hr. Following this pronounced mitochondrial fragmentation, Cd treatment led to signs of mitochondrial dysfunction, including excess reactive oxygen species (ROS) production, decreased ATP content, and mitochondrial membrane potential (▵Ψm) loss. However, 1 mM melatonin pretreatment efficiently attenuated the Cd-induced mitochondrial fragmentation, which improved the turnover of mitochondrial function. In the brain tissues of rats that were intraperitoneally given 1 mg/kg CdCl2 for 7 days, melatonin also ameliorated excessive mitochondrial fragmentation and mitochondrial damage in vivo. Melatonin's protective effects were attributed to its roles in preventing cytosolic calcium ([Ca(2+) ]i ) overload, which blocked the recruitment of Drp1 from the cytoplasm to the mitochondria. Taken together, our results are the first to demonstrate that abnormal mitochondrial dynamics is involved in cadmium-induced neurotoxicity. Melatonin has significant pharmacological potential in protecting against the neurotoxicity of Cd by blocking the disbalance of mitochondrial fusion and fission.
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Shangcheng
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Pi
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.|Cancer Institute of the People's Liberation Army, The Second Affiliated Hospital of Third Military Medical University, Chongqing, China.
authors.forename: Nixian
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Third Military Medical University, Chongqing, China.
authors.forename: YuMing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA.
authors.forename: Huiliang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Deng
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Mindi
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D034281:Dynamins / Q000378:metabolism*; D008550:Melatonin / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D024101:Mitochondrial Proteins; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D002104:Cadmium; C519851:Dnm1l protein, rat; D034281:Dynamins; D008550:Melatonin; D002118:Calcium
keywords: Drp1; cadmium; melatonin; mitochondrial dynamics; neurotoxicity