Evidence for non-transferrin-mediated uptake and release of iron and manganese in glial cell cultures from hypotransferrinemic mice.

Transferrin (Tf) is accepted as the iron mobilization protein, but its role in transport of other metals is controversial. In this study, we used mixed glial cultures from hypotransferrinemic (Hp) mice to determine the dependence of these cells on transferrin for iron and manganese delivery and release. Hp mice have a splicing defect in the transferrin (Tf) gene, resulting in < 1% of the normal plasma levels of Tf. Cellular iron and manganese uptake increases over 24 hr in cultures of normal and Hp glial cells in the presence of standard concentrations of Tf in the media; although total 59iron uptake in the Hp mouse cultures was 2X greater than normal, 54Mn uptake was similar between the two groups. The absence of Tf in the media resulted in a significant increase in 59iron uptake in both normal and Hp glial but did not affect Mn uptake. Elevated Tf (10X normal) in the media reduced both 59iron and 54Mn uptake. Efflux of 59Iron and 54Mn occurred in normal and Hp cultures, indicating the existence of a dynamic exchange of metals, and that intracellular Tf is not necessary for metal release. However, in the absence of Tf in the media, significantly more iron was retained in the cells than if Tf were present in both normal and Hp glial cultures. 54Mn release was minimally affected by extracellular Tf. The data demonstrate that Tf is not required for iron and Mn uptake into glial cells. These data further demonstrate a dynamic metal exchange system for glial cells which is not dependent on intracellular Tf.