Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport ManganeseSummary
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...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X2500030X |
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| author | Milankumar Prajapati Jared Z. Zhang Grace S. Chong Lauren Chiu Courtney J. Mercadante Heather L. Kowalski Olga Antipova Barry Lai Martina Ralle Brian P. Jackson Tracy Punshon Shuling Guo Mariam Aghajan Thomas B. Bartnikas |
| author_facet | Milankumar Prajapati Jared Z. Zhang Grace S. Chong Lauren Chiu Courtney J. Mercadante Heather L. Kowalski Olga Antipova Barry Lai Martina Ralle Brian P. Jackson Tracy Punshon Shuling Guo Mariam Aghajan Thomas B. Bartnikas |
| author_sort | Milankumar Prajapati |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bef332d656cd41bc91a93d526cd73df0 |
| institution | OA Journals |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-bef332d656cd41bc91a93d526cd73df02025-08-20T02:26:51ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-0119710148910.1016/j.jcmgh.2025.101489Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport ManganeseSummaryMilankumar Prajapati0Jared Z. Zhang1Grace S. Chong2Lauren Chiu3Courtney J. Mercadante4Heather L. Kowalski5Olga Antipova6Barry Lai7Martina Ralle8Brian P. Jackson9Tracy Punshon10Shuling Guo11Mariam Aghajan12Thomas B. Bartnikas13Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode IslandDepartment of Pathology and Laboratory Medicine, Brown University, Providence, Rhode IslandDepartment of Pathology and Laboratory Medicine, Brown University, Providence, Rhode IslandDepartment of Pathology and Laboratory Medicine, Brown University, Providence, Rhode IslandDepartment of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island; Currently at Ensoma, Boston, MassachusettsDepartment of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island; Currently at BlueRock Therapeutics, Cambridge, MassachusettsAdvanced Photon Source, Argonne National Laboratory, Argonne, IllinoisAdvanced Photon Source, Argonne National Laboratory, Argonne, IllinoisDepartment of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OregonBiomedical National Elemental Imaging Resource, Dartmouth College, Hanover, New HampshireBiomedical National Elemental Imaging Resource, Dartmouth College, Hanover, New HampshireIonis Pharmaceuticals, Inc., Carlsbad, CaliforniaIonis Pharmaceuticals, Inc., Carlsbad, CaliforniaDepartment of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island; Correspondence Address correspondence to: Thomas B. Bartnikas, MD, PhD, 70 Ship St. Box GE5, Providence, Rhode Island 02912; tel: (401) 863-3478.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.http://www.sciencedirect.com/science/article/pii/S2352345X2500030XAbsorptionHomeostasisMetal |
| spellingShingle | Milankumar Prajapati Jared Z. Zhang Grace S. Chong Lauren Chiu Courtney J. Mercadante Heather L. Kowalski Olga Antipova Barry Lai Martina Ralle Brian P. Jackson Tracy Punshon Shuling Guo Mariam Aghajan Thomas B. Bartnikas Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport ManganeseSummary Cellular and Molecular Gastroenterology and Hepatology Absorption Homeostasis Metal |
| title | Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport ManganeseSummary |
| title_full | Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport ManganeseSummary |
| title_fullStr | Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport ManganeseSummary |
| title_full_unstemmed | Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport ManganeseSummary |
| title_short | Studies of Slc30a10 Deficiency in Mice Reveal That Intestinal Iron Transporters Dmt1 and Ferroportin Transport ManganeseSummary |
| title_sort | studies of slc30a10 deficiency in mice reveal that intestinal iron transporters dmt1 and ferroportin transport manganesesummary |
| topic | Absorption Homeostasis Metal |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X2500030X |
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