Mathematical modeling of the relocation of the divalent metal transporter DMT1 in the intestinal iron absorption process

Abstract

Iron is essential for the normal development of cellular processes. This metal has a high redox potential that can damage cells and its overload or deficiency is related to several diseases, therefore it is crucial for its absorption to be highly regulated. A fast-response regulatory mechanism has been reported known as mucosal block, which allows to regulate iron absorption after an initial iron challenge. In this mechanism, the internalization of the DMT1 transporters in enterocytes would be a key factor. Two phenomenological models are proposed for the iron absorption process: DMT1’s binary switching mechanism model and DMT1’s swinging-mechanism model , which represent the absorption mechanism for iron uptake in intestinal cells. The first model considers mutually excluding processes for endocytosis and exocytosis of DMT1. The second model considers a Ball’s oscillator to represent the oscillatory behavior of DMT1’s internalization. Both models are capable of capturing the kinetics of iron absorption and represent empirical observations, but the DMT1’s swinging-mechanism model exhibits a better correlation with experimental data and is able to capture the regulatory phenomenon of mucosal block. The DMT1 swinging-mechanism model is the first phenomenological model reported to effectively represent the complexity of the iron absorption process, as it can predict the behavior of iron absorption fluxes after challenging cells with an initial dose of iron, and the reduction in iron uptake observed as a result of mucosal block after a second iron dose.

Co-Administration of Iron and a Bioavailable Curcumin Supplement Increases Serum BDNF Levels in Healthy Adults

“…Furthermore, with the reduced availability of apoferritin, the enterocytes' iron absorption would consequently reduce until the cells are replaced in 5 to 6 days [95] with their iron content being lost in the faeces. Nonetheless, the accuracy of mucosal block theory has been debated in recent studies [96][97][98]. However, in either case, reduced FIA or mucosal block could lead to the accumulation of large amounts of unabsorbed iron, which may cause gut inflammation [77], increase the production of free radicals in the mucosa (the innermost layer of the gut) [99,100] and may alter the gut microbiota by increasing pathogenic microorganisms whilst reducing commensal microflora [101,102].…”

Iron from the gut: the role of divalent metal transporter 1

“…The “mucosal block” hypothesis, which opposes transcytosis, is established by diminished intestinal iron absorption from orally administered iron to the body, likely due to exfoliative cell death in enterocytes. ( 42 , 58 , 59 ) Dietary iron overload significantly induced fetal gastrointestinal erosive hemorrhage in Dmt1-IRE transgenic (Tg) mice. ( 36 ) In contrast, in intestine-specific Irp KO mice, the mucosal block was withheld by a large excess of ferritin, but not by epithelial detachment.…”

Interaction between macrophages and ferroptosis

“…Iron is transported from extracellular environment into intracellular space through transferrin receptor 1 located on the cell membrane in the form of ferric ion (Fe 3+ ) [ 6 ], which is reduced to ferrous ion (Fe 2+ ) by ferric reductases such as STEAP3 in endosome [ 7 ] and then released into cytosol by divalent metal transporter 1 [ 8 ], participating in the synthesis of iron-dependent enzymes. The rest part of Fe 2+ is generally stored in the labile iron pool or ferritin composed of ferritin heavy chain 1 and ferritin light chain (FTL) [ 9 ].…”