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Correlation Between Attenuation of Protein Disulfide Isomerase Activity Through S-Mercuration and Neurotoxicity Induced by Methylmercury

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Abstract

Methylmercury (MeHg), an environmental pollutant, causes neuronal death via endoplasmic reticulum (ER) stress; however, the precise mechanism is not fully understood. The aim of this study was to elucidate the possible mechanism of MeHg-induced neurotoxicity. Treatment with MeHg resulted in a loss of cell viability in a concentration-dependent manner accompanying the expression of ER stress marker genes in human neuroblastoma SH-SY5Y cells. We next attempted to identify a target protein for MeHg in the ER. MeHg covalently modified protein disulfide isomerase (PDI), which is important for disulfide bond formation in nascent proteins in the ER lumen. S-Nitrosylation of the catalytic domains of PDI by nitric oxide was attenuated up to 50 % by a MeHg challenge in cells. The MeHg-modified C-terminal catalytic domain in PDI was detected by MALDI-TOF/MS. Furthermore, treatment with MeHg significantly attenuated the enzymatic activity of PDI. Taken together, these observations suggest that MeHg results in ER stress and following the unfolded protein response pathway via ER dysfunction due to S-mercuration of the C-terminus of PDI.

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Acknowledgments

We thank Aki Tsuboi and Yoko Okamoto for providing technical assistance. This work was supported in part by Grants-in Aid for Scientific Research on Challenging Exploratory Research 25670029 and Scientific Research B 22310093 from the Japan Ministry of Education, Culture, Sports and Technology (MEXT), by the Takeda Science Foundation, the Smoking Research Foundation, and the Okayama Medical Foundation.

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Authors and Affiliations

  1. Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    Kento Makino, Kosaku Okuda, Eisuke Sugino, Tadashi Nishiya & Takashi Uehara

  2. Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

    Takashi Toyama & Yoshito Kumagai

  3. Iwawaki Lab, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Japan

    Takao Iwawaki

  4. Department of Basic Medical Sciences, National Institute for Minamata Disease, Minamata, Japan

    Masatake Fujimura

Authors
  1. Kento Makino
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  2. Kosaku Okuda
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  3. Eisuke Sugino
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  4. Tadashi Nishiya
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  5. Takashi Toyama
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  6. Takao Iwawaki
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  7. Masatake Fujimura
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  8. Yoshito Kumagai
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  9. Takashi Uehara
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Corresponding author

Correspondence to Takashi Uehara.

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Kento Makino and Kosaku Okuda have contributed equally to this work.

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Makino, K., Okuda, K., Sugino, E. et al. Correlation Between Attenuation of Protein Disulfide Isomerase Activity Through S-Mercuration and Neurotoxicity Induced by Methylmercury. Neurotox Res 27, 99–105 (2015). https://doi.org/10.1007/s12640-014-9494-8

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  • DOI: https://doi.org/10.1007/s12640-014-9494-8

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