Iron homeostasis and nutritional iron deficiency

Abstract

Nonheme food ferritin (FTN) iron minerals, nonheme iron complexes, and heme iron contribute to the balance between food iron absorption and body iron homeostasis. Iron absorption depends on membrane transporter proteins DMT1, PCP/HCP1, ferroportin (FPN), TRF2, and matriptase 2. Mutations in DMT1 and matriptase-2 cause iron deficiency; mutations in FPN, HFE, and TRF2 cause iron excess. Intracellular iron homeostasis depends on coordinated regulation of iron trafficking and storage proteins encoded in iron responsive element (IRE)-mRNA. The noncoding IRE-mRNA structures bind protein repressors, IRP1 or 2, during iron deficiency. Integration of the IRE-RNA in translation regulators (near the cap) or turnover elements (after the coding region) increases iron uptake (DMT1/TRF1) or decreases iron storage/efflux (FTN/FPN) when IRP binds. An antioxidant response element in FTN DNA binds Bach1, a heme-sensitive transcription factor that coordinates expression among antioxidant response proteins like FTN, thioredoxin reductase, and quinone reductase. FTN, an antioxidant because Fe(2+) and O(2) (reactive oxygen species generators) are consumed to make iron mineral, is also a nutritional iron concentrate that is an efficiently absorbed, nonheme source of iron from whole legumes. FTN protein cages contain thousands of mineralized iron atoms and enter cells by receptor-mediated endocytosis, an absorption mechanism distinct from transport of nonheme iron salts (ferrous sulfate), iron chelators (ferric-EDTA), or heme. Recognition of 2 nutritional nonheme iron sources, small and large (FTN), will aid the solution of iron deficiency, a major public health problem, and the development of new policies on iron nutrition.

FIGURE 1

Food iron has multiple, different structures but inside enterocytes enters an iron pool for FPN export. The 3 best-known biochemical types of nutrition iron and abundant food sources are shown. Each is absorbed by a different mechanism: iron in heme (meat): PCP/HCP1 (SLC46A) transporter (9, 33), FTN, nonheme iron, mineralized ferric oxide in a protein, abundant in whole legume seeds: clathrin-dependent, receptor-mediated endocytosis (10), and nonheme iron in salts or chelators from supplements, which is absorbed by the DMT1 (SLC11A) transporter (7, 8).

FIGURE 2

FTN protein with caged nanominerals enters polarized cells intact. (A) A eukaryotic FTN protein cage with a single subunit shown in green; the panel is original and based on the author’s own work in (31) using PDB file 1MFR. (B) Soybean FTN shown entering the apical side of cultured, polarized Caco-2 cells incubated in transwell plates and incubated for 30 min at 37°C with 5 nmol/L SoyFTN and a Z projection obtained from integration of the confocal microscopy slices using with a fluorescent tagged antisoybean FTN antiserum (left) or Oregon-green 488 tagged FTN (FTN) (right). The panels are original and based on the author’s own work in (10); FTN absorption is a clathrin-dependent endocytic process (10).