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Methylmercury is a representative environmental pollutant that causes central nervous system (CNS) damage.1,2) Mercury in the natural world is transformed by bacterial action to methylmercury and accumulates along the food chain so that it is found at relatively high levels in large fish. In recent years, it has become a global problem, confirmed by CNS defects in babies born to mothers who consume large amounts of fish.3,4) Nevertheless, the mechanisms involved in methylmercury toxicity and the protection against it are mostly still unknown. We have found that the ubiquitin–proteasome system (UPS, a proteolytic system) and autophagy are involved in methylmercury toxicity.5-7) We have also reported that excessively induced autophagy may be involved in enhancing methylmercury toxicity.7) Chang et al. reported that methylmercury reduces the levels of mammalian target of rapamycin (mTOR, an autophagy inhibitor), thereby inducing autophagy.8) This results in the inhibition of differentiation of neural stem cells into neurons. In addition, it has been suggested that in astrocytes and murine embryonic fibroblasts, autophagy may be a defense mechanism in response to methylmercury toxicity.9,10) Autophagy is a system for degrading proteins in cells, serving to prevent the accumulation of hypersynthesized proteins and abnormal proteins generated by a variety of stresses.11) Autophagy also contributes to biological homeostasis, including in the performance of protein cycles during starvation states.12) It is known that autophagy is induced by the activation of AMP-activated protein kinase when cells experience hypoglycemic or hypoxic starvation states.13) It is further known that when there is recovery to a normal intracellular nutrition state, mTOR is activated, and autophagy induction is inhibited.14) mTOR is a serine–threonine kinase activated by protein kinase B (Akt).15) Moreover, it is known that Akt is activated via phosphatidylinositol-3,4,5-trisphosphate (PIP3), phosphorylated from phosphatidylinositol-4,5-bisphosphate (PIP2) by phosphoinositide 3-kinase (PI3K); this signaltransduction system is known as the PI3K/Akt/mTOR pathway.16) This pathway is known to be negatively controlled by a phosphatase called PTEN (phosphatase and tensin homolog deleted on chromosome 10).16) PTEN exists mainly in the cytoplasm. When PTEN moves to the cell membrane, by dephosphorylating PIP3 to PIP2, it inhibits Akt activation.17) In recent years, many reports have emerged that PTEN functional abnormalities resulting in hyperactivation of Akt and causing progression of cancer.18-20) This suggests the involvement of autophagy inhibition mediated by Akt hyperactivation.21) Intracellular levels of PTEN are regulated by the UPS. Involved in this process, as a ubiquitin ligase, is a neural precursor cell-expressed developmentally down-regulated protein 4-1 (NEDD4-1).22) It is reported that NEDD4-1 levels increase by oxidative stress, and then ubiquitination of PTEN is proRegular Article

Methylmercury Induces Cytotoxicity through Inhibition of PTEN Activity by a Decrease in Its Solubility