Iron transport into the cells is strictly regulated by specific carriers at any level. The expression of the various carriers varies from tissue to tissue.
Cytoplasmic iron is defined as transit/labile iron pool and it is very short lived.
Mechanisms involved in cellular iron uptake
- Transferrin-bound iron uptake
- Non-transferrin iron uptake
- Free iron
- Free heme
- Transport of other iron complexes
- Heme-hemopexin complex
- Haemoglobin-haptoglobin complex
from Liver iron transport 2007
Cellular iron transport.
- (1) TFR1-mediated uptake of diferric transferrin . Diferric transferrin binds to its specific receptor and is endocytosed. The endosome is acidified and Fe3+ is reduced by STEAP3 . The iron is released and transported out of the endosome via DMT1 and apotransferrin is exocytosed.
- (2) TFR2-mediated uptake of transferrin . This mechanism is similar to the TFR1-specific mechanism except that transferrin binds to TFR2.
- (3) Uptake of NTBI . Iron is reduced and is transported into the cell via a carrier-mediated process.
- (4) Uptake of ferritin . Ferritin binds to its specific receptor and is endocytosed. The endosome is directed to lysosomes and the iron is transferred to the transit pool or endogenous ferritin.
- (5) Uptake of haem-haemopexin . The haem-haemopexin complex binds to its specific receptor CD91 and is endocytosed. Haem is removed and is degraded by haem oxygenase.
- (6) Uptake of haemoglobin-haptoglobin . The haemoglobin-haptoglobin complex binds to a specific receptor. Following endocytosis, the complex may be directed to the canalicular membrane for release into the bile or to the lysosomes for degradation.
- (7) Uptake of lactoferrin . Lactoferrin binds to LRP or RHL-1 and is endocytosed and targeted to the lysosomes for degradation.
- (8) . Iron is released by FPN and oxidised by caeruloplasmin and binds to apotransferrin .
TFR1 transferrin receptor 1; TFR2 transferrin receptor 2; STEAP3 six-transmembrane epithelial antigen of the prostate 3; DMT1 divalent metal transporter 1; NTBI non-transferrin bound iron; ZIP14 zinc-regulated transporter and iron-regulated transporter-like protein 14; LRP low-density lipoprotein receptor-related protein; FPN ferroportin.
Transferrin-bound iron uptake
Transferrin mediated Iron uptake is a multistep process
1. Transferrin binding
Transferrin Receptor 1 (High affinity transferrin uptake)
- HFE - Haemochromatosis Protein
- HFE interacts with the helical domain of TFR1, competing with transferrin for its binding site. The resulting inhibition causes a reduction in transferrin-bound iron uptake in a variety of cell types, suggesting that HFE is involved in the regulation of iron uptake by TFR1, possibly by limiting the amount of iron released from transferrin. A mutation in HFE was the fi rst to be shown to be causative for the iron overload disorder, haemochromatosis.
Transferrin Receptor 2 (Low affinity transferrin uptake)
2. Iron reduction
- STEAP3 - Ferrireductase
- STEAP3, six-transmembrane epithelial antigen of the prostate 3 is a ferrireductase.
Following endocytosis and vesicle acidification, iron is reduced to its ferrous form by STEAP3 prior to being transferred across the endosomal membrane. At endosomal pH, the reduction potential of ferric iron co-ordinated by transferrin is increased when diferric transferrin is complexed to TFR1, suggesting that reduction of iron occurs prior to release from transferrin.
3. Divalent Iron transport
DMT1 - Divalent metal transporter 1
* The released ferrous iron is transported from the interior of the endosome to the cytosol by DMT1 (also known as natural resistance-associated macrophage protein 2 NRAMP2 , divalent cation transporter 1 DCT1 , or solute carrier family 11 member 2 SLC11A2 ).
DMT1 appears to be regulated by iron levels with protein expression increased in iron loaded liver, lower in control liver, and not detected in iron deficient livers.
Non-transferrin iron uptake
Fig.1 The cellular mechanisms involved in NTBI . Non-haem iron (mostly ferric) is reduced by the actions of the ferric reductase Dcytb and reducing agents in the diet to yield Fe2+, which subsequently enters the enterocytes via DMT1 . Haem is absorbed via HCP1 , broken down by haem oxygenase 1 (HO) to liberate Fe2+ (this joins a common pool with iron from the non-haem pathway) and bilirubin (which might be removed from the cell by the efflux proteins FLVCR and ABCG2 ). If body iron stores are high, iron may be diverted into ferritin and lost when the cell is shed at the villus tip. Alternatively, iron passes into the labile iron pool (LIP) and is subsequently processed for efflux via IREG1 (as Fe2+). The exiting iron is re-oxidised to Fe3+ through hephaestin (Hp) to enable loading onto transferrin (Tf) . (Iron output)
- Ferrous Iron - Ferric Iron - Dcytb/DMT1
Fe3+ is thought to be essentially non-bioavailable and, therefore, it must first be converted to ferrous iron prior to absorption.
Ferric iron may still be reduced by tha cells endogenous reducing activity, a ferric reductase enzymic activity: Dcytb ( for ), a homologue of cytochrome b561.
Like cytochrome b561, Dcytb is a haemcontaining protein with putative binding sites for ascorbate and semi-dehydroascorbate. [P Sharp, SK Srai, 2007].
Following reduction either by Dcytb, the resulting Fe2+ becomes a substrate for the divalent metal transporter DMT1 -also known as the divalent cation transporter DCT1 , and natural resistance associated macrophage protein Nramp2 . DMT1 is an electrogenic transporter that transports divalent cations in symport with a single proton. Thus, it requires a pH gradient (at least pH 6 vs. pH 7.4: pH optimum 5.5) for transport and is not functional at neutral pH [R Fuchs et al, 2004; P Sharp, SK Srai, 2007].
- Haem - HCP1/haem oxygenase 1
The mechanisms involved in haem iron absorption are only just beginning to emerge. Haem binds to the duodenal brush border membrane and is absorbed as an intact molecule.
A number of candidate haem binding proteins have been identified in the intestinal epithelial cells including the haem carrier protein HCP1 that acts as a haem import protein, its high duodenal expression suggests that it may be the protein involved in haem uptake from the diet. However, the precise role of HCP1 in iron metabolism remains to be fully elucidated.
Following absorption, haem is detectable in membrane-bound vesicles within the cytoplasm. Within these vesicles, it is thought that the iron contained with the protoporphyrin ring is excised by the action of haem oxygenase 1 yielding ferrous iron which enters a common intracellular pool along with the iron absorbed via the non-haem transport pathways.
Digestion appears to be complete within the enterocytes, actually there are other 2 haem binding proteins on the basolateral membrane: the ATP-binding cassette protein ABCG2 , the feline leukaemia virus C receptor protein FLVCR and one possibility is that the efflux proteins ABCG2 and FLVCR, also expressed in the duodenum, may act to remove bilirubin formed as a by-product of haem degradation from the enterocytes. [P Sharp, SK Srai, 2007]
Transport of other iron complexes
Ferritin is the major iron storage protein. Ferritin is a 24-subunit protein that is capable of binding up to 4,600 Fe(III) ions.
The ferritin iron uptake mechanism is yet to be determined.
Cells clear ferritin by a method involving binding to a specific ferritin receptor followed by endocytosis.There are several possible fates for endocytosed ferritin including catabolism of the protein in lysosomes, excretion in the bile or inclusion in the endogenous ferritin pool. Any iron released is distributed to the mitochondria and endogenous ferritin.
One possibility is that ferritin is broken down by protease activity in the upper gastrointestinal tract and the released iron is absorbed via the Dcytb/DMT1 route.
However, studies have shown that ferritin is largely resistant to high temperature, low pH and protein denaturing agents. Therefore, it is possible that ferritin may be absorbed intact and broken down intracellularly (in the lysosomes) to liberate its iron load.
While the presence of ferritin receptors has been postulated on liver and placental plasma
membranes, none has yet been identified in intestinal tissue. [P Sharp, SK Srai, 2007; BA Syed et al 2006]
The uptake of the haem-haemopexin complex is mediated by its specific receptor, CD91. Following endocytosis, haem is degraded by haem oxygenase.
Haemopexin is substantially degraded in lysosomes.
- Haemoglobin-haptoglobin complex
The haemoglobin-haptoglobin complex also binds to a high-affinity specific receptor and is endocytosed. However, from this point, two possibilities exist for the fate of the complex. Both haemoglobin and haptoglobin may be directed to lysosomes for degradation or transported to the canalicular membrane of hepatocytes where haemoglobin is released into the bile and the receptor is recycled to the sinusoidal membrane.
Lactoferrin is an iron-binding protein similar to transferrin which is present mainly in
Lactoferrin is capable of binding two ferric ions. Specific receptors for lactoferrin have been identified on the brush border surface of foetal enterocytes, these receptors mediate the uptake of lactoferrin-bound iron.The lactoferrin receptor may be the principal iron transport pathway in early life. [P Sharp, SK Srai, 2007]
Two lactoferrin binding sites have been reported, although neither is specific for lactoferrin. The first is low-density lipoprotein receptor-related protein (LRP) and the second is the major ( RHL-1 ) subunit of the asialoglycoprotein receptor. Lactoferrin appears to be cleared via receptor-mediated endocytosis regardless of its binding site. Most of the internalised lactoferrin is directed to lysosomes for degradation.