Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

Abstract

Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

Keywords: apoptosis; cell signaling; manganese; neuroinflammation; neurotoxicity.

Figure 1

Neuroinflammatory effects of Mn exposure. NF-κB activation through a number of mechanisms plays a key role in proinflammatory effects of Mn [81]. Specifically, Mn overload significantly increased IkBα degradation ultimately resulting in NF-κB activation [82]. In addition, Mn-induced mitochondrial dysfunction and ROS overproduction also contributes to activation of redox-active NF-κB. Mn was also shown to activate JAK2/STAT3 pathway [83]. Both of these mechanisms may underlie Mn-induced proinflammatory cytokine overproduction. Recent studies have also clarified the particular role of NLRP3 inflammasome activation in Mn-induced neuroinflammation and pyroptosis. Activation of NLRP3 inflammasome under Mn exposure may result not only from NF-κB-induced NLRP3 expression, but also due to exosomal transport of ACS protein from other exposed cells [90]. Mn overexposure and oxidative stress provide significant damage to lysosomes with subsequent increase in membrane permeability and cathepsin B release. The latter also up-regulates NLRP3-inflammasome activation [91].

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].

Figure 3

Mechanisms of Mn-induced apoptosis. Mn exposure results in mitochondrial dysfunction and Bax-associated cytochrome c leakage with subsequent caspase 9 and 3 activation resulting in apoptosis. Mn-induced apoptosis may be aggravated by stimulatory effects of manganese on p53 protein as well as down-regulation of murine double minute 2 (Mdm2) homolog and wild-type p53-induced phosphatase 1 (Wip1) protein, both having inhibitory influence on p53 [140]. The impact of Mn on p53 signaling may be also mediated by Mn-dependent modulation of ataxia telangiectasia mutated (ATM) kinase [71]. In turn, Mn may decrease anti-apoptotic effects of Bcl2 and BDNF through inhibiting CREB phosphorylation and subsequent down-regulation of Bcl2 and BDNF expression [137]. It has been also demonstrated that mitochondrial pathway of apoptosis may be also aggravated by Mn-induced alteration of mitofusin 2 (Mfn2) expression, a protein involved in mitochondrial fusion and functioning [134].

Figure 4

The impact of manganese overexposure on glutamate-glutamine cycle. Manganese exposure results in a significant increase in glutamate levels through down-regulation of glutamine synthetase (GS) [179] and glutamate dehydrogenase (GDH) [182] along with up-regulation of glutaminase [179]. These effects result in reduced glutamate-to-glutamine conversion as well as glutamate catabolism in Krebs cycle through the formation of α-ketoglutarate. Mn-induced inhibition of astrocyte glutamate uptake results from inhibition of glutamine transporters (GLT1 and GLAST). Recent studies demonstrated that this inhibitory effect may be mediated through NF-κB-dependent activation of Yin Yang 1 (YY1) transcription factor [173] and ephrin A3 [178]. It is also notable that Mn-induced NF-κB signaling also plays a significant role in astrocyte activation associated with reduced glutamine synthetase activity [181].