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Bryan Mackenzie, PhDAssociate Professor Department of Molecular and Cellular Physiology
Iron deficiency is the most prevalent micronutrient deficiency worldwide. The iron transporter DMT1 is the primary route of uptake in the intestine. DMT1 is also responsible for mobilization of iron from the endosome to cytosol, a crucial step in the transferrin-associated uptake of iron in erythroid precursor cells. Export of iron from enterocytes and from macrophages (recycling iron from senescent red blood cells) is thought to be mediated by ferroportin (Fpn). Whereas Fpn was identified a decade ago, very little is known about how this transporter works. Dr. Mackenzie’s interests lie in the molecular mechanisms, substrate selectivity and structure-function of DMT1 and Fpn. These studies will reveal how these transporters function in diverse environments and how they may contribute to the etiology of iron-overload disorders, and will help drive the development of novel approaches to improve metal-ion nutrition, and treat iron overload or heavy-metal intoxication. He uses the voltage clamp, radiotracer assays and fluorescence-based assays in RNA-injected Xenopus oocytes, together with the use of genetically modified animal models (including the intestine-specific DMT1 knockout mouse and intestinal Na+/H+ exchanger nulls).
Dr. Mackenzie collaborates with Dr. Montrose utilizing the live microscopy core for live-imaging of metal-ion transport using fluorescent probes. Additionally, he works with Dr. Shull studying iron homeostasis in genetically-modified mouse models. Anticipated Core use: Integrative Morphology Core.
click image to enlarge
Effects of calcium on DMT1-mediated H+ leak and Fe2+-evoked currents associated with expression of human DMT1 in RNA-injected Xenopus oocytes. (A) Typical continuous current recordings at membrane potential (Vm) of −70 mV in a control oocyte (i) and in an oocyte expressing DMT1 (ii). Oocytes were superfused with Ca2+-free medium at pH 7.5 for the periods shown by the empty bars, or with Ca2+-free medium at pH 5.5 (hatched bars). 20 mM Ca2+ is indicated by the gray bars and 20 μM or 2 μM Fe2+, by the black bars. Figure from Biochem Biophys Res Commun, 2010;393:471-475.
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