SIRT1 downregulation mediated Manganese-induced neuronal apoptosis through activation of FOXO3a-Bim/PUMA axis

Abstract

Manganese (Mn) is an essential trace element. Excessive exposure to Mn may lead to neuronal death and neurodegenerative disorders. Accumulating evidence has shown that silent mating type information regulation 2 homolog 1 (SIRT1) plays a vital role in brain damage. However, whether aberrant SIRT1 levels contribute to Mn-induced neurotoxicity remains unknown. In this study, we report the important role of SIRT1 downregulation during Mn-induced neuronal apoptosis. Mn was found to downregulate SIRT1 protein levels in the rat pheochromocytoma (PC12) cells and mouse brain tissues. Mn enhanced SIRT1 protein degradation and downregulated its gene expression. Furthermore, Mn induced cell apoptosis in a dose-dependent manner both in vitro and in vivo, and resulted in an increase in forkhead box O (FOXO) 3a expression and acetylation. SIRT1 activation by resveratrol clearly attenuated Mn-triggered apoptosis and FOXO3a activation. Mn markedly increased the expression of Bcl-2 interacting mediator of cell death (Bim) and p53-up-regulated modulator of apoptosis (PUMA), whereas downregulation of FOXO3a significantly inhibited their upregulation and subsequent apoptosis. In summary, we determined that Mn downregulated SIRT1 by multiple mechanisms, thus led to apoptosis via activation of the FOXO3a–Bim/PUMA axis in PC12 cells. These findings on the impact of Mn on SIRT1 may lead to an improved understanding of Mn-induced neurotoxicity and provide a molecular target to antagonise Mn-associated neuronal damage.