Abstract
BackgroundHeme and non-heme iron from diet, and recycled iron from hemoglobin are important products of the synthesis of iron-containing molecules. In excess, iron is potentially toxic because it can produce reactive oxygen species through the Fenton reaction. Humans can absorb, transport, store, and recycle iron without an excretory system to remove excess iron. Two candidate heme transporters and two iron transporters have been reported thus far. Heme incorporated into cells is degraded by heme oxygenases (HOs), and the iron product is reutilized by the body. To specify the processes of heme uptake and degradation, and the reutilization of iron, we determined the subcellular localizations of these transporters and HOs.ResultsIn this study, we analyzed the subcellular localizations of 2 isoenzymes of HOs, 4 isoforms of divalent metal transporter 1 (DMT1), and 2 candidate heme transporters--heme carrier protein 1 (HCP1) and heme responsive gene-1 (HRG-1)--in non-polarized and polarized cells. In non-polarized cells, HCP1, HRG-1, and DMT1A-I are located in the plasma membrane. In polarized cells, they show distinct localizations: HCP1 and DMT1A-I are located in the apical membrane, whereas HRG-1 is located in the basolateral membrane and lysosome. 16Leu at DMT1A-I N-terminal cytosolic domain was found to be crucial for plasma membrane localization. HOs are located in smooth endoplasmic reticulum and colocalize with NADPH-cytochrome P450 reductase.ConclusionsHCP1 and DMT1A-I are localized to the apical membrane, and HRG-1 to the basolateral membrane and lysosome. These findings suggest that HCP1 and DMT1A-I have functions in the uptake of dietary heme and non-heme iron. HRG-1 can transport endocytosed heme from the lysosome into the cytosol. These localization studies support a model in which cytosolic heme can be degraded by HOs, and the resulting iron is exported into tissue fluids via the iron transporter ferroportin 1, which is expressed in the basolateral membrane in enterocytes or in the plasma membrane in macrophages. The liberated iron is transported by transferrin and reutilized for hemoglobin synthesis in the erythroid system.
Highlights
Heme and non-heme iron from diet, and recycled iron from hemoglobin are important products of the synthesis of iron-containing molecules
Our results suggest that heme carrier protein 1 (HCP1) functions on the apical membrane of enterocytes, heme responsive gene-1 (HRG-1) transports heme from the inside of the lysosome into the macrophages, and heme oxygenase (HO) on smooth endoplasmic reticulum (ER) catalyze the degradation of heme in the cytosol
green fluorescent protein (GFP)-tagged HO-1 completely colocalized with NADPH-cytochrome P450 reductase (Figure. 1A, a-c) and partly colocalized with syntaxin 17 (Figure. 1A, g-i) and calnexin (Figure. 1A, j-k)
Summary
Heme and non-heme iron from diet, and recycled iron from hemoglobin are important products of the synthesis of iron-containing molecules. To specify the processes of heme uptake and degradation, and the reutilization of iron, we determined the subcellular localizations of these transporters and HOs. Iron has an essential function in mammalian metabolism because of the ease with which it can gain and lose electrons. Iron is indispensable for eukaryotes and prokaryotes; it is potentially toxic because of the generation of the superoxide anion and hydroxyl radical. These oxygen metabolites humans occurs through exfoliation of enterocytes and skin cells, and through menstruation and childbirth. DMT1 is highly conserved from prokaryotes to eukaryotes, expressed in the apical membrane of absorptive enterocytes in the small intestine, and is present in the endosomes of all human cells [8]. Hepcidin induces irreversible internalization of FPN1 through lysosomal degradation, which results in a depletion of plasma iron and an accumulation of iron in duodenal enterocytes and macrophages [13]
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