Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria

Shangcheng Xu, Huifeng Pi, Lei Zhang, Nixian Zhang, Yu Ming 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 YuZhou Zhou

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

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 (ΔΨm) 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.

Original languageEnglish (US)
Pages (from-to)291-302
Number of pages12
JournalJournal of pineal research
Volume60
Issue number3
DOIs
StatePublished - Apr 2016

Keywords

  • Drp1
  • cadmium
  • melatonin
  • mitochondrial dynamics
  • neurotoxicity

ASJC Scopus subject areas

  • Endocrinology

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