Influence of iron metabolism on manganese transport and toxicity

Abstract

Although manganese (Mn) is critical for the proper functioning of various metabolic enzymes and cofactors, excess Mn in the brain causes neurotoxicity. While the exact transport mechanism of Mn has not been fully understood, several importers and exporters for Mn have been identified over the past decade. In addition to Mn-specific transporters, it has been demonstrated that iron transporters can mediate Mn transport in the brain and peripheral tissues. However, while the expression of iron transporters is regulated by body iron stores, whether or not disorders of iron metabolism modify Mn homeostasis has not been systematically discussed. The present review will provide an update on the role of altered iron status in the transport and toxicity of Mn.

Figure 1. Proposed mechanisms of Mn-iron interaction

The structural and chemical similarities between Mn and iron allow them to interact with each other in biological systems. Both Mn and iron can be transported as divalent forms by several divalent metal transporters (e.g. DMT1 and FPN) or as trivalent forms by the Tf/TfR system. It has been known that iron status can alter the expression of these transporters, thereby modifying Mn levels in the body. In addition, both Mn and iron serve as cofactors for several metalloproteins that play critical roles in antioxidant defense and neurological function. Since many of these enzymes have binding affinities for both metals, it is possible that they can substitute each other under certain conditions (dotted arrows), thereby alter the activity of these enzymes.

Figure 2. Absorption, distribution and disposal of Mn

Mn is absorbed via intestinal, pulmonary and olfactory transport. At the intestine lumen, free Mn or lactoferrin-bound Mn can be taken into the enterocytes via divalent metal transporter 1 (DMT1), ZIP8 and lactoferrin receptor. The free Mn inside the enterocytes is released into blood for systemic circulation. Airborne Mn, especially Mn particles, is absorbed through the lung by inhalation. While both DMT1 and transferrin receptor (TfR) are expressed at the epithelial cells and transferrin (Tf) is found in bronchoalveolar fluid, it is unclear whether they are directly involved in pulmonary Mn transport. Ferroprotein (FPN) is expressed at the alveolar macrophages, where it could contribute to dissolution of Mn-containing particles and thereby absorption of soluble Mn. DMT1 is involved in the olfactory uptake of Mn into blood and brain. The nasal route also expresses several metal transporters, including FPN and ZIPs, but their roles in olfactory Mn transport have not been evaluated. Mn can be directly taken up into the brain by calcium channels expressed at the terminal of olfactory nerves. After absorption, Mn distributes into the tissues by several importers. Intracellular Mn is released into blood or excreted out of the body by metal exporters, such as FPN and SLC30A10. The liver is the major organ for Mn disposal, and Mn is mainly excreted by the bile into the feces. However, the exact mechanism of biliary Mn secretion is unknown. The mechanism of Mn uptake/export in the brain is incompletely understood and results are controversial.

Figure 3. Impact of iron status on Mn-associated neurotoxicity

Changes in iron homeostasis or gene mutations in iron transporters and regulatory proteins can alter the expression of metal transporters that mediate the import and export of Mn, which thereby influences the absorption, distribution and disposal of Mn. Consequently, Mn homeostasis in the brain could be perturbed, and the neurotoxicity associated with Mn accumulation could be altered.