Involvement of autophagy via mammalian target of rapamycin (mTOR) inhibition in tributyltin-induced neuronal cell death.

Tributyltin chloride (TBT) is a neurotoxic environmental pollutant that inhibits mitochondrial adenosine triphosphate (ATP) synthase. Autophagy is one of the major protein degradation systems induced by a decrease of intracellular ATP following activation of AMP-activated protein kinase (AMPK). Because we previously found that TBT induces activation of AMPK, here we examined whether TBT induces autophagic neuronal death. Exposure of cortical neurons to 500 nM TBT reduced the phosphorylation of mammalian target of rapamycin (mTOR), a regulator of autophagy. An autophagy inhibitor, 3-methyladenine (3-MA), markedly decreased TBT-induced neuronal death. TBT also induced the formation of LC3-II, an autophagy marker. These results suggest that TBT-induced neuronal death is at least partly autophagic.