Interactions between iron and manganese in neurotoxicity

The essential and naturally occurring transition metal manganese (Mn) is present in the soil, water, air, and various foods. Manganese can accumulate in the brain if the Mn intake or exposure is excessive and this can result in neurotoxic effects. Manganese is important for the proper activation of different metabolic and antioxidant enzymes. There are numerous Mn importers and exporters. However, the exact transport mechanism for Mn is not fully understood. On the other hand, iron (Fe) is another well-known essential metal, which has redox activity in addition to chemical characteristics resembling those of Mn. Existing data show that interactions occur between Fe and Mn due to certain similarities regarding their mechanisms of the absorption and the transport. It has been disclosed that Mn-specific transporters, together with Fe transporters, regulate the Mn distribution in the brain and other peripheral tissues. In PC12 cells, a significant increase of transferrin receptor (TfR) mRNA expression was linked to Mn exposure and accompanied by elevated Fe uptake. In both humans and animals, there is a strong relationship between Fe and Mn metabolism. In the present review, special attention is paid to the interaction between Mn and Fe. In particular, Fe and Mn distribution, as well as the potential molecular mechanisms of Mn-induced neurotoxicity in cases of Fe deficiency, are discussed.