Biomedical Engineering Reference
In-Depth Information
The FLVCR receptor is required for terminal RBC development [
139
]. It is
also involved in proerythroblast survival. It facilitates macrophage recycling of
heme iron [
140
]. Moreover, FLVCR intervenes in the recycling of heme iron from
senescent RBCs.
The export of heme is preferentially boosted by hemopexin [
140
]. Hemopexin
abounds in serum (concentration 6-25
mol; 0.4-1.5 mg/ml in humans). It accepts
heme from FLVCR and carries it to the liver, thereby ensuring iron homeostasis, in
addition to its scavenger role during internal bleeding and hemolysis.
Heme synthesis must be coordinated with translation of globin proteins to avoid
toxic accumulation of hemoglobin precursors. Heme synthesis begins and ends in
mitochondria, but several intermediate steps happen in the cytoplasm. Hemoglobin
precursors are then transported across the mitochondrial membrane. The terminal
step of heme synthesis in mitochondria corresponds to insertion of an imported
iron atom into protoporphyrin-9. It is catalyzed by mitochondrial ferrochelatase,
an integral protein of the inner mitochondrial membrane.
Transporter SLC25a37, or mitoferrin (Mfrn1), transfers ferrous iron (Fe
2
+
)
across the mitochondrial membrane. The ATP-binding cassette transporter ABCb10
stabilizes the mitochondrial iron transporter SLC25a37 at least in erythroid pre-
cursors [
141
]. Both SLC25a37 and ABCb10 not only can homodimerize, but also
complex with other partners. The SLC25a37-ABCb10 complex yields iron to
ferrochelatase, thereby allowing erythroid precursors to accelerate their production
of heme. Ferrochelatase, or protoheme ferrolyase, catalyses the terminal step
(stage 8) of heme synthesis, converting protoporphyrin-9 into heme. Ferrochelatase
is a partner for both SLC25a37 and ABCb10 transporters that forms the Fech-
SLC25a37-ABCb10 complex [
142
]. Iron import in mitochondria is thus synergisti-
cally integrated with heme synthesis.
3.5.7.3
Functional and Dysfunctional Hemoglobin Types
Hemoglobin has many functional and dysfunctional types (Tables
3.4
and
3.5
). The
globin gene loci comprise mainly the
-
globin locus on chromosome 11. About 400 alteration types of hemoglobin genes
have been detected.
Synthesis of
α
-globin locus on chromosome 16 and
β
chain begins late in the third trimester in utero. In the first
8 weeks, majority of the hemoglobin is embryonic hemoglobin (hemoglobin-E). In
the embryo, hemoglobin variants comprise hemoglobin Gower-1 (
δ
ζ
2
2
) and Gower-
2(
α
2
2
), as well as hemoglobin Portland (
ζ
2
γ
2
). In the fetus, fetal hemoglobin, or
hemoglobin-F (
α
2
γ
2
), is produced. In newborns, hemoglobin-F is nearly completely
replaced by adult hemoglobin in week 12 of postnatal life. Fetal hemoglobin binds
oxygen with greater affinity than adult hemoglobin.
In adults, hemoglobin-F is restricted to a limited population of F reticulocytes
and erythrocytes. Hemoglobin-A2 (
α
2
δ
2
) is an adult variant (1.5-3.5%).
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