Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 9 Iron Metabolism and Its Disorders
In contrast, only about 3% of the iron in plasma results
from enterocyte absorption in normal individuals ( Ponka et
al ., 1998 ).
V. REGULATION OF IRON METABOLISM
A. Intracellular Regulation of
Iron Metabolism
1 . Cytoplasmic Regulation of Iron
The synthesis of a number of proteins important in iron
metabolism, including apotransferrin, TfR1, apoferritin,
DMT1, DcytB, ferroportin, iron responsive protein-1 (IRP1),
and erythroid-specific 5-aminolevulinic acid synthase (eALAS
or ALAS2), is regulated posttranscriptionally depending on
intracellular iron content ( Beutler, 2006b ; Koury and Ponka,
2004 ; Latunde-Dada et al ., 2006a ). The mRNA for each protein
contains one or more iron responsive elements (IREs),
each consisting of a stem-loop structure. The IREs located at
the 5 end of mRNAs regulate translation, and IREs located
at the 3 end regulate mRNA stability. IRP1 contains an
Fe-S (4Fe-4S) cluster and exhibits aconitase activity when
cells are iron replete, but it lacks the Fe-S cluster and aconitase
activity when cytoplasmic iron is scarce. IRP1 binds
tightly to IREs when cytoplasmic iron content is low. IRP2
is closely related to IRP1, but it lacks aconitase activity. The
regulation of IRP2 is mediated by proteosomal degradation
when cellular iron is adequate, through binding to iron and
possibly heme ( Wingert et al ., 2005 ). The binding of IRPs
to IREs at the 5 end of mRNAs (including apoferritin and
eALAS) inhibits translation and protein synthesis from these
mRNAs, but the binding of IRPs to IREs at the 3 end of
mRNAs (including TfR1 and intestinal DMT1) promotes
mRNA stability, thereby enhancing protein synthesis from
these mRNAs. When cytoplasmic iron content is high, IRPs
are displaced from IREs, resulting in opposite effects on
protein synthesis ( Starzynski et al ., 2004 ). Because of these
controlling factors, TfR1 synthesis is higher and apoferritin
synthesis is lower when cytoplasmic iron content is low, and
TfR1 synthesis is lower and apoferritin synthesis is higher
when cytoplasmic iron content is high ( Napier et al ., 2005 ).
2 . Mitochondrial Iron Metabolism and
Regulation
Mitochondria are clearly central in the intracellular metabolism
of iron; however, much remains to be discovered
about their iron metabolism. The first enzyme reaction in
heme synthesis (ALAS) and the final three enzyme reactions
(including the insertion of Fe 2 into protoporphyrin
IX by ferrochelatase to form heme) occur within mitochondria
(see Chapter 8 for details), and proteins involved in
Fe-S cluster synthesis are located within mitochondria.
Fe-S cluster synthesis has been studied in microbes, but
this pathway has not been well characterized in mammals.
An inherited defect in a small protein called frataxin causes
Friedreich ataxia in humans ( Napier et al ., 2005 ). This
disorder results in spino/cerebellar ataxia, cardiomyopathy,
and diabetes associated with mitochondrial iron overload
in nerve and cardiac tissue, but not in erythroid cells.
Frataxin participates in the synthesis of Fe-S clusters, possibly
as a mitochondrial iron chaperone that shields this
metal from reactive oxygen species and renders it bioavailable
as Fe 2 (Napier et al ., 2005 ). Heme and Fe-S clusters
synthesized within mitochondria are used locally and
exported from mitochondria for insertion into cytoplasmic
and nuclear enzymes. With the exception of a limited number
of enzymes, such a ribonucleotide reductase, that have
mono- or di-iron-binding sites, iron in heme and Fe-S clusters
accounts for most of the enzyme iron. Consequently,
almost all of the iron within cells must transit through mitochondria
to be functionally active ( Arosio and Levi, 2002 ).
Mitoferrin, a member of the vertebrate mitochondrial
solute carrier family (SLC25), appears to be essential for
the uptake of iron into mitochondria ( Shaw et al ., 2006 ).
The transporter needed to export heme from mitochondria
to the cytoplasm is unknown; however, an inner mitochondrial
membrane ATP-binding cassette protein B7 (ABCB7)
appears to be required as an exporter for Fe-S clusters
(Napier et al ., 2005 ). Studies in a zebra fish shiraz model
indicate that heme synthesis in erythroid cells is dependent
on the production of Fe-S clusters ( Wingert et al ., 2005 ).
Deficient Fe-S cluster formation (resulting from glutaredoxin
5 deficiency) and the resultant deficiency of Fe-S clusters
in the cytoplasm of developing erythroid cells result in
IRP1 binding to IREs of eALAS and the inhibition eALAS
translation. A deficiency in eALAS activity in zebra fish erythroid
cells results in deficient heme synthesis and the formation
of hypochromic erythrocytes ( Wingert et al ., 2005 ).
A human with mitochondrial glutaredoxin 5 deficiency has
recently been described with sideroblast-like microcytic anemia
and iron overload ( Camaschella et al ., 2007 ).
Mitochondria can store excess iron using mitochondrial
ferritin (m-ferritin). Unlike cytoplasmic apoferritin, mitochondrial
apoferritin lacks an IRE and may be transcriptionally
regulated by iron. M-ferritin forms homopolymeric
shells that have more homology with cytoplasmic H-ferritin
chains than L-ferritin chains ( Napier et al ., 2005 ). M-ferritin
concentration is very low in most cells, including erythroid
cells, but it is markedly increased in disorders with mitochondrial
iron overload, presumably limiting the oxidative
damage generated by the excess iron. M-ferritin appears to
be degraded to hemosiderin-like material within mitochondria,
but the mechanism is unknown ( Napier et al ., 2005 ).
B. Systemic Regulation of Iron Metabolism
Hepcidin, a small antimicrobial peptide secreted by hepatocytes
into the circulation, is an important regulator