Manganese transport in eukaryotes: The role of DMT1

Abstract

Manganese (Mn) is a transition metal that is essential for normal cell growth and development, but is toxic at high concentrations. While Mn deficiency is uncommon in humans, Mn toxicity is known to be readily prevalent due to occupational overexposure in miners, smelters and possibly welders. Excessive exposure to Mn can cause Parkinson's disease-like syndrome; patients typically exhibit extrapyramidal symptoms that include tremor, rigidity and hypokinesia (Calne et al., 1994;Dobson et al., 2004).Mn-induced motor neuron diseases have been the subjects of numerous studies; however, this review is not intended to discuss its neurotoxic potential or its role in the etiology of motor neuron disorders. Rather, it will focus on Mn uptake and transport via the orthologues of the divalent metal transporter (DMT1) and its possible implications to Mn toxicity in various categories of eukaryotic systems, such as in vitro cell lines, in vivo rodents, the fruitfly, Drosophila melanogaster, the honeybee, Apis mellifera L., the nematode, Caenorhabditis elegans, and the baker's yeast, Saccharomyces cerevisiae. Keywords DMT1; Manganese; NRAMP-2; Transport ManganeseMn is one of the most abundant naturally occurring elements in the earth's crust; it does not occur naturally in a pure state. Oxides, carbonates and silicates are the most important Mncontaining minerals (Post, 1999). Depending on its oxidation state, Mn is utilized in countless industrial processes, such as the production of dry cell batteries, steel (Post, 1999; Saric, 1986), fuel oil additives and antiknock agents (Pfeifer et al., 2004;Ressler et al., 1999;Rollin et al., 2005). *Corresponding Author: Michael Aschner, PhD, 2215-B Garland Avenue, 11425 MRB IV, Vanderbilt University Medical Center, Nashville, michael.aschner@vanderbilt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurotoxicology. Author manuscript; available in PMC 2009 July 1. Published in final edited form as:Neurotoxicology. 2008 July ; 29(4): 569-576. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe major source of Mn in humans is through dietary ingestion. Approximately 3-5% of ingested Mn is absorbed across the intestinal wall, and the remainder is excreted in feces, representing tight homeostatic control over Mn absorption. Mn toxicity from dietary intake is rare; its uptake is tightly regulated, and any excess of ingested Mn is readily excreted via the bile. In contrast, both pulmonary uptake and particulate transport via the olfactory bulb (Saric, 1986;Aschner et al., 1991...

Caenorhabditis elegans: An Emerging Model System for Pesticide Neurotoxicity

“…Manganese exposure by itself has been shown to result in a variety of detrimental effects in C. elegans [146][147][148]. One study demonstrates that even short exposures (30 min) to manganese result in production of ROS, as evidenced by a drastic increase in glutathione levels [143].…”

“…elegans studies have also confirmed that manganese exposure may have an additive effect on DAergic neurodegeneration in neurons containing α-synuclein protein aggregates. Various labs have concluded that the C. elegans SMF-1 transporter, an analogue of the divalent metal transporter (DMT-1) found in humans, is important in the degeneration of these neurons [146,147,149,150]. Results in C. elegans indicate that this transporter plays a significant role in neurotoxicity by transporting manganese into the cell where it can induce numerous intracellular changes.…”

Imaging neuronal pathways with 52Mn PET: Toxicity evaluation in rats

“…Being a paramagnetic substance, it reduces the spin-lattice relaxation time (T1) of surrounding water protons and, therefore, acts as a contrast agent in T1-weighted magnetic resonance (MR) images (Pautler et al, 1998, Saleem et al, 2002. When administered to the neural tissue, Mn 2+ enters neurons via different types of ion channels, including voltagegated calcium channels (Drapeau and Nachshen, 1984, Narita et al, 1990, Crossgrove and Yokel, 2005, as well as metal transporters, including divalent metal transporter 1 (DMT1) (Garrick et al, 2003, Au et al, 2008. Most importantly for neuroscientific studies, Mn 2+ is further transported by neural cells and can cross synapses (Sloot and Gramsbergen, 1994, Pautler et al, 1998, Saleem et al, 2002, which is not the case for all divalent metal ions (Tjalve et al, 1996).…”

Effect of hemochromatosis on manganese neurotoxicity

“…Mn can reach the central nerve system (CNS) through DMT1 and/or TfR1 -mediated endocytosis (Diagram 3) [16,186]. Other transporters that can facilitate Mn entry to the CNS are store-operated and voltage-gated calcium channels [187,188], the choline transporter [189,190], citrate transporter [191] and ionotropic glutamate receptor Ca 2+ channels [192].…”

“…Within the brain, Mn binds to brain Tf which can mediate the neuronal uptake of Mn through TfR1 uptake mechanism that requires DMT1 for the metal export from the endosomes into the cytoplasm [15,186,199]. Also, DMT1 can facilitate Mn accumulation in DA-rich areas [200].…”