Manganese homeostasis and transport

Abstract

The review addresses issues pertinent to Mn accumulation and its mechanisms of transport, its neurotoxicity and mechanisms of neurodegeneration. The role of mitochondria and glia in this process is emphasized. We also discuss gene x environment interactions, focusing on the interplay between genes linked to Parkinson's disease (PD) and sensitivity to Mn.

Figure 1.

Transport mechanisms responsible for the uptake of Mn. Tf – transferrin; TfR transferrin receptor; DMT1-divalent metal transporter 1; VR -voltage gated Ca⁺² channel; SOC – store operated Ca⁺² channel; Glu Rec – glutamic acid ionotropic receptor.

Figure 2.

Mechanism for the transport of Mn across the intestine.

Figure 3.

Schematic representation of some cellular mechanisms vulnerable to the toxic effects of Mn. Pathway 1 represents the mitochondrial toxic action with decreased in ATP production and glutathione levels (GSH) leading to cytochrome c release and caspase activation and apoptosis. Pathway 2 represents endoplasmic reticulum stress with increased expression of glucose-regulated protein (GRP78) and pro-apoptotic protein C/EBP homologous protein (CHOP). Pathway 3 represents Mn clastogenic effect. Pathway 4 represents fibrillation of α-synuclein protein leading to the formation of cytoplasmatic inclusions. Pathway 5 represents microglial activation with the release of pro inflammatory mediators as interleukin-6 (IL6), interleukin-1β (IL1β) and tumor necrosis factor α (TNF α).