Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport Manganese.

BACKGROUND & AIMS: SLC11A2 (DMT1) and SLC40A1 (ferroportin) are essential for dietary iron absorption, but their role in manganese transport is debated. SLC30A10 deficiency causes severe manganese excess due to loss of gastrointestinal manganese excretion. Patients are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here, we determine if divalent metal transport 1 (Dmt1) and ferroportin can transport manganese using Slc30a10-deficient mice as a model. METHODS: Manganese absorption and levels and other disease parameters were assessed in Slc30a10(-/-) mice with and without intestinal Dmt1 and ferroportin deficiency using gastric gavage, surgical bile collections, multiple metal assays, and other techniques. The contribution of intestinal Slc30a10 deficiency to ferroportin-dependent manganese absorption was explored by determining if intestinal Slc30a10 deficiency increases manganese absorption in a mouse model of hereditary hemochromatosis, a disease of iron excess due to ferroportin upregulation. RESULTS: Manganese absorption was increased in Slc30a10-deficient mice despite manganese excess. Intestinal Dmt1 and ferroportin deficiency attenuated manganese absorption and excess in Slc30a10-deficient mice. Intestinal Slc30a10 deficiency increased manganese absorption and levels in the hemochromatosis mouse model. CONCLUSIONS: Aberrant absorption contributes prominently to SLC30A10 deficiency, a disease previously attributed to impaired excretion, and is dependent upon intestinal Dmt1 and ferroportin and exacerbated by loss of intestinal Slc30a10. This work expands our understanding of overlaps between manganese and iron transport and the mechanisms by which the body regulates absorption of 2 nutrients that can share transport pathways. We propose that a reconsideration of the role of Dmt1 and ferroportin in manganese homeostasis is warranted.