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Review
. 2015 Mar 31;7(4):2274-96.
doi: 10.3390/nu7042274.

Duodenal cytochrome b (DCYTB) in iron metabolism: an update on function and regulation

Darius J R Lane  1 , Dong-Hun Bae  2 , Angelica M Merlot  3 , Sumit Sahni  4 , Des R Richardson  5
Affiliations
Review

Duodenal cytochrome b (DCYTB) in iron metabolism: an update on function and regulation

Darius J R Lane et al. Nutrients. .

Abstract

Iron and ascorbate are vital cellular constituents in mammalian systems. The bulk-requirement for iron is during erythropoiesis leading to the generation of hemoglobin-containing erythrocytes. Additionally; both iron and ascorbate are required as co-factors in numerous metabolic reactions. Iron homeostasis is controlled at the level of uptake; rather than excretion. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance non-heme iron absorption in the gut; ascorbate regulates iron homeostasis. The involvement of ascorbate in dietary iron absorption extends beyond the direct chemical reduction of non-heme iron by dietary ascorbate. Among other activities; intra-enterocyte ascorbate appears to be involved in the provision of electrons to a family of trans-membrane redox enzymes; namely those of the cytochrome b561 class. These hemoproteins oxidize a pool of ascorbate on one side of the membrane in order to reduce an electron acceptor (e.g., non-heme iron) on the opposite side of the membrane. One member of this family; duodenal cytochrome b (DCYTB); may play an important role in ascorbate-dependent reduction of non-heme iron in the gut prior to uptake by ferrous-iron transporters. This review discusses the emerging relationship between cellular iron homeostasis; the emergent "IRP1-HIF2α axis"; DCYTB and ascorbate in relation to iron metabolism.

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Figures

Figure 1
Figure 1
The role of duodenal cytochrome b561 (DCYTB) as a transplasma membrane oxidoreductase. DCYTB is transplasma membrane oxidoreductase that reduces either extracellular ferric iron, (Fe(III)), cupric copper (Cu(II)), or the ascorbyl radical (AR), at the expense of intracellular reducing equivalents derived proximally from intracellular ascorbate and/or quercetin, or possibly dihydrolipoic acid (DHLA). The source of reducing equivalents for the recycling of intracellular ascorbate from dehydroascorbate (DHA) or AR includes reduced glutathione (GSH), which becomes oxidized to GSSG, and/or NAD(P)H, which becomes oxidized to NAD(P)+, but also the mitochondrial respiratory chain (not shown). For a review on intracellular ascorbate recycling, see Linster [16] and Lane and Lawen [15].
Figure 2
Figure 2
Model for the IRP1-HIF2α axis in regulating DCYTB and dietary iron absorption. (A) Under conditions of iron deficiency (as well as hypoxia or increased erythropoietic drive), the expression of HIF2α is increased in the duodenal enterocyte. This leads to transcriptional up-regulation of key iron-metabolism proteins, including DCYTB, DMT1 and FPN1. Specifically, the increase in HIF2α leads to an augmentation of DCYTB and DMT1 in the brush border (i.e., apical) membrane of the duodenal enterocyte and an increase in FPN1 levels in the basolateral membrane. HIF2α has been shown to bind to HRE elements in the regulatory regions of the promoters for DCYTB and DMT1. HIF2α is also regulated at the post-transcriptional level (as a consequence of the IRE in its 5′-UTR) and post-translational level (as a consequence of PHD activity). Under conditions of iron deficiency in the duodenum, although the increased IRE-binding activity of the IRP1 would tend to decrease HIF2α translation, the stabilizing effect of low PHD activity on HIF2α protein levels may predominate, leading to a net increase in HIF2α and a consequent up-regulation of DCYTB and DMT1. (B) In contrast, under conditions of high iron in the duodenum, HIF2α is translationally derepressed by IRP1, yet PHD activity is likely to be increased, leading to increased HIF2α hydroxylation and proteasomal degradation. The net effect is a decrease in HIF2α levels, resulting in decreased DCYTB, DMT1 and perhaps FPN1 levels.
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