Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium‐dependent translocation of Drp1 to the mitochondria |
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| Authors: | Shangcheng Xu Huifeng Pi Lei Zhang Nixian Zhang YuMing Li Huiliang Zhang Ju Tang Huijuan Li Min Feng Ping Deng Pan Guo Li Tian Jia Xie Mindi He Yonghui Lu Min Zhong Yanwen Zhang Wang Wang Russel J. Reiter Zhengping Yu Zhou Zhou |
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| Affiliation: | 1. Department of Occupational Health, Third Military Medical University, Chongqing, China;2. Cancer Institute of the People's Liberation Army, The Second Affiliated Hospital of Third Military Medical University, Chongqing, China;3. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Third Military Medical University, Chongqing, China;4. Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, USA;5. Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA |
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| 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 ([Ca2+]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. |
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| Keywords: | cadmium Drp1 melatonin mitochondrial dynamics neurotoxicity |
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