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, 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 & 1 others Zhou Zhou

Research output: Contribution to journalArticle

53 Citations (Scopus)

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 ((up triangle, open)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.

Original languageEnglish (US)
JournalJournal of Pineal Research
DOIs
StateAccepted/In press - 2016

Fingerprint

Mitochondrial Dynamics
Melatonin
Cadmium
Mitochondria
Calcium
Cadmium Chloride
Mitochondrial Turnover
Mitochondrial Membrane Potential
Neurodegenerative Diseases
Reactive Oxygen Species
Cytoplasm
Adenosine Triphosphate
Pharmacology
Pathology
Neurons
Brain

Keywords

  • Cadmium
  • Drp1
  • Melatonin
  • Mitochondrial dynamics
  • Neurotoxicity

ASJC Scopus subject areas

  • Endocrinology

Cite this

Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria. / Xu, Shangcheng; Pi, Huifeng; Zhang, Lei; Zhang, Nixian; Li, Yuming; Zhang, Huiliang; Tang, Ju; Li, Huijuan; Feng, Min; Deng, Ping; Guo, Pan; Tian, Li; Xie, Jia; He, Mindi; Lu, Yonghui; Zhong, Min; Zhang, Yanwen; Wang, Wang; Reiter, Russel J; Yu, Zhengping; Zhou, Zhou.

In: Journal of Pineal Research, 2016.

Research output: Contribution to journalArticle

Xu, S, Pi, H, Zhang, L, Zhang, N, Li, Y, Zhang, H, Tang, J, Li, H, Feng, M, Deng, P, Guo, P, Tian, L, Xie, J, He, M, Lu, Y, Zhong, M, Zhang, Y, Wang, W, Reiter, RJ, Yu, Z & Zhou, Z 2016, 'Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria', Journal of Pineal Research. https://doi.org/10.1111/jpi.12310
Xu, Shangcheng ; Pi, Huifeng ; Zhang, Lei ; Zhang, Nixian ; Li, Yuming ; Zhang, Huiliang ; Tang, Ju ; Li, Huijuan ; Feng, Min ; Deng, Ping ; Guo, Pan ; Tian, Li ; Xie, Jia ; He, Mindi ; Lu, Yonghui ; Zhong, Min ; Zhang, Yanwen ; Wang, Wang ; Reiter, Russel J ; Yu, Zhengping ; Zhou, Zhou. / Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria. In: Journal of Pineal Research. 2016.
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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 ((up triangle, open)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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T1 - Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria

AU - Xu, Shangcheng

AU - Pi, Huifeng

AU - Zhang, Lei

AU - Zhang, Nixian

AU - Li, Yuming

AU - Zhang, Huiliang

AU - Tang, Ju

AU - Li, Huijuan

AU - Feng, Min

AU - Deng, Ping

AU - Guo, Pan

AU - Tian, Li

AU - Xie, Jia

AU - He, Mindi

AU - Lu, Yonghui

AU - Zhong, Min

AU - Zhang, Yanwen

AU - Wang, Wang

AU - Reiter, Russel J

AU - Yu, Zhengping

AU - Zhou, Zhou

PY - 2016

Y1 - 2016

N2 - 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 ((up triangle, open)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.

AB - 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 ((up triangle, open)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.

KW - Cadmium

KW - Drp1

KW - Melatonin

KW - Mitochondrial dynamics

KW - Neurotoxicity

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DO - 10.1111/jpi.12310

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