title: Transport of pyruvate into mitochondria is involved in methylmercury toxicity.
abstract: We have previously demonstrated that the overexpression of enzymes involved in the production of pyruvate, enolase 2 (Eno2) and D-lactate dehydrogenase (Dld3) renders yeast highly sensitive to methylmercury and that the promotion of intracellular pyruvate synthesis may be involved in intensifying the toxicity of methylmercury. In the present study, we showed that the addition of pyruvate to culture media in non-toxic concentrations significantly enhanced the sensitivity of yeast and human neuroblastoma cells to methylmercury. The results also suggested that methylmercury promoted the transport of pyruvate into mitochondria and that the increased pyruvate concentrations in mitochondria were involved in intensifying the toxicity of methylmercury without pyruvate being converted to acetyl-CoA. Furthermore, in human neuroblastoma cells, methylmercury treatment alone decreased the mitochondrial membrane potential, and the addition of pyruvate led to a further significant decrease. In addition, treatment with N-acetylcysteine (an antioxidant) significantly alleviated the toxicity of methylmercury and significantly inhibited the intensification of methylmercury toxicity by pyruvate. Based on these data, we hypothesize that methylmercury exerts its toxicity by raising the level of pyruvate in mitochondria and that mitochondrial dysfunction and increased levels of reactive oxygen species are involved in the action of pyruvate.
authors.affiliation: Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.|Laboratory of Pharmaceutical Health Sciences, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.|School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0232, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Naganuma
authors.affiliation: Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Gi-Wook
authors.initials: GW
authors.lastname: Hwang
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000111:Acetylcysteine / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D045022:Lactate Dehydrogenases / Q000378:metabolism; D008767:Methylmercury Compounds / Q000378:metabolism / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D000975:Antioxidants; D008767:Methylmercury Compounds; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D045022:Lactate Dehydrogenases; C071195:D-lactate dehydrogenase; D010751:Phosphopyruvate Hydratase; C516797:enolase 2, S cerevisiae; D000111:Acetylcysteine