RGD Reference Report - Temporal responses in the disruption of iron regulation by manganese. - Rat Genome Database

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Temporal responses in the disruption of iron regulation by manganese.

Authors: Kwik-Uribe, Catherine  Smith, Donald R 
Citation: Kwik-Uribe C and Smith DR, J Neurosci Res. 2006 Jun;83(8):1601-10.
RGD ID: 12904041
Pubmed: PMID:16568477   (View Abstract at PubMed)
DOI: DOI:10.1002/jnr.20836   (Journal Full-text)

Manganese (Mn) is an essential trace element, though at elevated exposures it is also a neurotoxicant. Several mechanisms underlying manganese toxicity have been investigated, although a consistent mechanism(s) of action at low exposures has not been fully elucidated. Here we systematically evaluated the effects of in vitro manganese exposure on intracellular iron (Fe) homeostasis and iron-regulatory protein (IRP) binding activity in undifferentiated PC12 cells over a range of manganese exposure concentrations (1, 10, 50, and 200 microM MnCl(2)) and exposure durations (12, 24, 36, and 48 hr), to test the hypothesis that moderately elevated manganese exposure disrupts cellular iron regulation. Results demonstrate that manganese exposure produces a rapid and sustained dose-dependent dysregulation of cellular iron metabolism, with effects occurring as early as 12 hr exposure and at manganese doses as low as 1 microM. Manganese exposure altered the dynamics of IRP-1 binding and the intracellular abundance of IRP-2, and altered the cellular abundance of transferrin receptor, ferritin, and mitochondrial aconitase protein levels. Cellular levels of labile iron were significantly increased with manganese exposure, although total cellular iron levels were not. The overall pattern of effects shows that manganese produced an inappropriate cellular response akin to iron deficiency, to which the cells were able to mount a compensatory response. Consistent with our previous studies, these data indicate that even low to moderate exposures to Manganese in vitro significantly disrupt cellular iron metabolism, which may be an important contributory mechanism of manganese neurotoxicity.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ireb2Ratcellular response to manganese ion  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ireb2  (iron responsive element binding protein 2)


Additional Information