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The Functional Properties and Intestinal Role of the H+-Coupled Divalent Metal-Ion Transporter 1, DMT1

Shawki, Ali
http://orcid.org/0000-0002-6413-5313
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1448037106

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Systems Biology and Physiology.
Iron is an essential micronutrient in higher organisms. Despite its abundance on Earth, its bioavailability to mammals is poor. Thus, mammals have evolved specialized systems to acquire and conserve iron; however, too much iron is toxic. Iron deficiency is the most prevalent micronutrient deficiency worldwide. Deficiency of this metal results in iron-deficiency anemia, and neurological and developmental disorders in infants and children. But too much iron—such as occurs in hemochromatosis or thalassemia—results in liver cirrhosis, hepatocellular cancer, cardiomyopathy, endocrine disorders (e.g. diabetes), skin disorders, and joint disorders. This thesis examines the role of DMT1 in iron homeostasis. I tested the hypothesis that intestinal DMT1 is required for the absorption of iron, copper, manganese, and zinc by examining metal metabolism and directly measuring intestinal absorption of radiotracer metals in the DMT1int/int mouse. I demonstrate here that DMT1 serves as the primary or only gateway for the absorption of nonheme iron from the diet, but that DMT1 is not required for the absorption of copper, manganese, or zinc. DMT1 is driven by the proton electrochemical gradient in vitro; however, the provenance of the protons in vivo is unknown. I explored the role of the brush-border Na+/H+ exchangers in iron absorption and metabolism. I demonstrate that the activity of DMT1 relies on the acidic microclimate at the brush border of the small intestine generated by Na+/H+ exchanger-3. The critical roles of DMT1 are evident in animal models and human probands bearing DMT1 mutations that lead to severe iron-deficiency anemia. I demonstrate that human mutations in DMT1, in general, result in impaired iron-transport activity of DMT1. My analysis of the impact of DMT1 mutations helps to explain the anemia phenotype of the probands but also uncovers novel aspects of the molecular physiology of DMT1. Dysregulation of iron sensing can lead to upregulation of DMT1 and consequently iron overload (e.g. hereditary hemochromatosis, thalassemia, sickle-cell disease). DMT1 is a validated target in the treatment of iron overload. The outcome of this work will help drive the development of therapies for improved iron nutrition and the treatment or prevention of iron overload.
Bryan Mackenzie, Ph.D. (Committee Chair)
Tomas Ganz, M.D. Ph.D. (Committee Member)
Hamid Eghbalnia, Ph.D. (Committee Member)
Rohit Kohli, M.B.B.S. M.S. (Committee Member)
Anil Menon, Ph.D. (Committee Member)
Gary Edward Shull, Ph.D. (Committee Member)
153 p.
Physiological Psychology
homeostasis; iron; nutrition; absorption; metabolism; transport

Recommended Citations

Citations

  • Shawki, A. (2015). The Functional Properties and Intestinal Role of the H+-Coupled Divalent Metal-Ion Transporter 1, DMT1 [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1448037106

    APA Style (7th edition)

  • Shawki, Ali. The Functional Properties and Intestinal Role of the H+-Coupled Divalent Metal-Ion Transporter 1, DMT1. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1448037106.

    MLA Style (8th edition)

  • Shawki, Ali. "The Functional Properties and Intestinal Role of the H+-Coupled Divalent Metal-Ion Transporter 1, DMT1." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1448037106

    Chicago Manual of Style (17th edition)

ucin1448037106
975
© 2015, some rights reserved.Creative Commons License The Functional Properties and Intestinal Role of the H+-Coupled Divalent Metal-Ion Transporter 1, DMT1 by Ali Shawki is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.