Mathematical modeling reveals ferritin as the strongest cellular driver of dietary iron transfer block in enterocytes

Intestinal mucosal block is the transient reduction in iron absorption ability of intestinal epithelial cells (enterocytes) in response to previous iron exposures that occur at the cell scale. The block characteristics have been shown to depend both on iron exposure magnitude and temporality, and understanding block control will enable deeper understanding of how intestinal iron absorption contributes to pathological iron states. Three biochemical mechanisms implicated in driving the block behavior are divalent metal transporter 1 endocytosis, ferritin iron sequestration, and iron regulatory protein regulation of iron related protein expression. In this work, a model of enterocyte iron metabolism is built based on published experimental data that is capable of reproducing the mucosal block phenomena. The model is then used to estimate the quantitative contribution of each of the three mechanisms on the properties of the mucosal block. Analysis reveals that ferritin and iron regulatory proteins are the main intracellular mechanisms contributing to the mucosal block, findings congruent with experimental predictions. Lastly, DMT1 endocytosis is shown to play a role in limiting total iron uptake by enterocytes but does not contribute to the decrease in total iron transfer across their basal membrane seen in the mucosal block.