Cadmium induced inhibition of autophagy is associated with microtubule disruption and mitochondrial dysfunction in primary rat cerebral cortical neurons

Recent studies have reported that mitochondria serve as direct targets for cadmium- (Cd-) induced neuronal toxicity, which can be attenuated by autophagy. The molecular mechanisms' underlying Cd-induced mitochondrial dysfunction and autophagy in neurons are not known. In this study, we studied the upstream signaling pathways induced by Cd-mediated mitochondrial metabolism alterations using primary rat neuron as a model. We found that Cd induced the destruction of microtubules (MTs), and resulted in tau hyper-phosphorylation and decreased acetylated tubulin levels, which were related to a decrease in mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels. As a result of taxol disruption, alterations in macroautophagy, like altered cellular distribution of the autophagy-related protein light chain 3 beta (LOB) and the expression of Atg5 were found compared with Cd group. We found for the first time that MT disruption induced by Cd reduced the levels of autophagy, leading to mitochondrial dysfunction. These observations suggest new therapeutic strategies aimed to activate or ameliorate pro-survival macroautophagy. (C) 2015 Elsevier Inc. All rights reserved.