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Increased putrescine levels due to ODC1 overexpression prevents mitochondrial dysfunction-related apoptosis induced by methylmercury.
Life Sci. 2020 Jun 29 [Online ahead of print]LS

Abstract

AIMS

We had previously reported that addition of putrescine to the culture medium was reported to reduce methylmercury toxicity in C17.2 neural stem cells. Here, we have examined the inhibition of methylmercury-induced cytotoxicity by putrescine using ODC1-overexpressing C17.2 cells.

MATERIALS AND METHODS

We established stable ODC1-overexpressing C17.2 cells and evaluated methylmercury-induced apoptosis by examining the TUNEL assay and cleaved caspase-3 levels. Mitochondria-mediated apoptosis was also evaluated by reduction of mitochondrial membrane potential and recruitment of Bax and Bak to the mitochondria.

KEY FINDINGS

ODC is encoded by ODC1 gene, and putrescine levels in ODC1-overexpressing cells were significantly higher than in control cells. Overexpression of ODC1 and addition of putrescine to the culture medium suppressed DNA fragmentation and caspase-3 activation, which are observed when apoptosis is induced by methylmercury. Moreover, mitochondrial dysfunction and reactive oxygen species (ROS) generation, caused by methylmercury, were also inhibited by the overexpression of ODC1 and putrescine; pretreatment with ODC inhibitor, however, promoted both ROS generation and apoptosis by methylmercury. Finally, we found that Bax and Bak, the apoptosis-promoting factors, to be increased in mitochondria, following methylmercury treatment, and the same was inhibited by overexpression of ODC1. These results suggest that overexpression of ODC1 may prevent mitochondria-mediated apoptosis by methylmercury via increase of putrescine levels.

SIGNIFICANCE

Our findings provide important clues to clarify mechanisms involved in the defense against methylmercury toxicity and suggest novel biological functions of putrescine.

Authors+Show Affiliations

Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan; Inhalation Toxicology Research Group, Korea Institute of Toxicology, 30, Baekhak1-gil Jeongeup-si, Jeollabuk-do 56212, Republic of Korea.Laboratory of Pharmaceutical Health Sciences, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.Laboratory of Environmental and Molecular Toxicology, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan.Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan; Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: hwang@tohoku-mpu.ac.jp.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32615186

Citation

Sato, Masayuki, et al. "Increased Putrescine Levels Due to ODC1 Overexpression Prevents Mitochondrial Dysfunction-related Apoptosis Induced By Methylmercury." Life Sciences, 2020, p. 118031.
Sato M, Toyama T, Kim MS, et al. Increased putrescine levels due to ODC1 overexpression prevents mitochondrial dysfunction-related apoptosis induced by methylmercury. Life Sci. 2020.
Sato, M., Toyama, T., Kim, M. S., Lee, J. Y., Hoshi, T., Miura, N., Naganuma, A., & Hwang, G. W. (2020). Increased putrescine levels due to ODC1 overexpression prevents mitochondrial dysfunction-related apoptosis induced by methylmercury. Life Sciences, 118031. https://doi.org/10.1016/j.lfs.2020.118031
Sato M, et al. Increased Putrescine Levels Due to ODC1 Overexpression Prevents Mitochondrial Dysfunction-related Apoptosis Induced By Methylmercury. Life Sci. 2020 Jun 29;118031. PubMed PMID: 32615186.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased putrescine levels due to ODC1 overexpression prevents mitochondrial dysfunction-related apoptosis induced by methylmercury. AU - Sato,Masayuki, AU - Toyama,Takashi, AU - Kim,Min-Seok, AU - Lee,Jin-Yong, AU - Hoshi,Takayuki, AU - Miura,Nobuhiko, AU - Naganuma,Akira, AU - Hwang,Gi-Wook, Y1 - 2020/06/29/ PY - 2020/04/28/received PY - 2020/06/25/revised PY - 2020/06/27/accepted PY - 2020/7/3/entrez PY - 2020/7/3/pubmed PY - 2020/7/3/medline KW - Apoptosis KW - Methylmercury KW - Mitochondria KW - ODC1 KW - Putrescine SP - 118031 EP - 118031 JF - Life sciences JO - Life Sci. N2 - AIMS: We had previously reported that addition of putrescine to the culture medium was reported to reduce methylmercury toxicity in C17.2 neural stem cells. Here, we have examined the inhibition of methylmercury-induced cytotoxicity by putrescine using ODC1-overexpressing C17.2 cells. MATERIALS AND METHODS: We established stable ODC1-overexpressing C17.2 cells and evaluated methylmercury-induced apoptosis by examining the TUNEL assay and cleaved caspase-3 levels. Mitochondria-mediated apoptosis was also evaluated by reduction of mitochondrial membrane potential and recruitment of Bax and Bak to the mitochondria. KEY FINDINGS: ODC is encoded by ODC1 gene, and putrescine levels in ODC1-overexpressing cells were significantly higher than in control cells. Overexpression of ODC1 and addition of putrescine to the culture medium suppressed DNA fragmentation and caspase-3 activation, which are observed when apoptosis is induced by methylmercury. Moreover, mitochondrial dysfunction and reactive oxygen species (ROS) generation, caused by methylmercury, were also inhibited by the overexpression of ODC1 and putrescine; pretreatment with ODC inhibitor, however, promoted both ROS generation and apoptosis by methylmercury. Finally, we found that Bax and Bak, the apoptosis-promoting factors, to be increased in mitochondria, following methylmercury treatment, and the same was inhibited by overexpression of ODC1. These results suggest that overexpression of ODC1 may prevent mitochondria-mediated apoptosis by methylmercury via increase of putrescine levels. SIGNIFICANCE: Our findings provide important clues to clarify mechanisms involved in the defense against methylmercury toxicity and suggest novel biological functions of putrescine. SN - 1879-0631 UR - https://www.unboundmedicine.com/medline/citation/32615186/Increased_putrescine_levels_due_to_ODC1_overexpression_prevents_mitochondrial_dysfunction-related_apoptosis_induced_by_methylmercury L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(20)30781-5 DB - PRIME DP - Unbound Medicine ER -
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