Figure 2.

The potential mechanisms of Mn-induced oxidative stress. (A) Mn overexposure increases electron leakage and superoxide generation at electron transport chain complex II and increases MnSOD-dependent hydrogen peroxide formation [94,95]. Depression of antioxidant enzymes and loss of low-molecular weight antioxidants in response to Mn exposure also contribute to increased ROS accumulation [94]. (B) Mn increases adrenaline oxidation to adrenochrome with subsequent overproduction of superoxide [97]. (C) The impact of Mn on redox homeostasis may also be regulated at transcriptional level. Specifically, Mn-induced sirtuin down-regulation [98] results in increased acetylation of FOXO3a and PGC1α. Increased PGC1a acetylation is associated with reduced Nrf2 expression and down-regulation of Nrf2 target genes including γ-glutamylcysteine synthetase (γ-GCS), glutathione peroxidase (GPX), glutathione reductase (GR), glutathione synthetase (GS), NAD(P)H Quinone Dehydrogenase 1 (NQO-1), heme oxygenase 1 (HO-1) [98]. Mn exposure may also affect Nrf2 signaling through alterations of Keap1 expression [98]. In turn, increased FOXO3a acetylation results in decreased SOD and catalase expression that are up-regulated by deacetylated form, as well as promotes proapoptotic signaling through Bim and PUMA [103].