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NR 4-6/2009
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Iron and age-related
macular degeneration
Żelazo i zwyrodnienie plamki
związane z wiekiem
Błasiak Janusz1, Skłodowska
Anna2, Ulińska Magdalena2, Szaflik Jacek
P.2
1 Department of Molecular Genetics, University of
Lodz, Lodz, Poland
Head: Professor Janusz Błasiak, PhD
2 Ophthalmology Department, Medical University of
Warsaw, Warsaw, Poland
Head: Professor Jerzy Szaflik, MD, PhD |
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| Summary: |
Iron can be involved in
the pathogenesis of age-related macular degeneration (AMD)
through the oxidative stress. In siderosis, exogenous
iron can cause retinal degeneration which can be also
associated with elevated retinal iron levels resulting
in hereditary defects in iron homeostasis. Iron is
transported into the retina by the endocytosis of iron
complexed with transferrin and stored in complex with
ferritin. The retinal pigmented epithelium and the
neuroretinal vasculature serve as blood-retina barriers
and disruption of homeostasis at these barriers may
result in iron overload. There is firm experimental
evidence that retinas of AMD patients contain more iron
than retinas of the healthy subjects, but the question
whether it is the reason or a consequence of AMD remains
open. Excessive iron can cause damage to protein, lipids
and DNA through the generation of free radicals in the
Fenton reaction. Therefore, iron may play a role in the
pathogenesis of AMD as a source of free radical damage
but this hypothesis has not been verified experimentally
and further studies are needed to establish the
relationship between disturbance in iron homeostasis and
AMD. |
| Słowa kluczowe: |
age related macular
degeneration, AMD, iron ions, oxidative stress,
transferring, ferritin, RPE cells, celuroplazmin, DNA
damage. |
| Key words: |
zwyrodnienie plamki
związane z wiekiem, AMD, jony żelaza, stres oksydacyjny,
transferryna, ferrytyna, komórki RPE, celuroplazmina,
uszkodzenia DNA. |
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Introduction
Age-related macular degeneration (AMD) is a disease of the
central retina, the macula, characterized by progressive
degeneration of the retina, retinal pigmented epithelium (RPE)
and choroid. On the degeneration of the macula, central vision
is impaired, or even lost, and peripheral vision dominates, or
remains. In addition to central vision impairment, AMD patients
suffer also from impairment of distance visual acuity, near
visual acuity, color discrimination, contrast sensitivity and
other sense functions. They have problems with reading,
recognizing other people’s faces, playing or even watching
sports (1). It is considered as the main cause of vision loss
and blindness in individuals aged over 65 (2). Mechanisms
underlying occurrence and progression of this disease are
largely unknown.
Oxidative stress and damage caused by its product, mainly
reactive oxygen species (ROS), may be implicated in the
pathogenesis of AMD, but this concept remains unproven (3). High
polyunsaturated fatty acid content in photoreceptor outer
segments combined with oxygen-rich environment may provide
reactive oxygen species, but the source of oxidative stress
playing a role in the pathogenesis of AMD is still unknown.
There are experimental data and hypotheses on several factors,
which can contribute to this disease, with iron ions among them.
Iron homeostasis
Iron is an element which is essential for cellular homeostasis.
The lack of it may lead to serious disturbances in the cell’s
functioning, which, in consequence, may result in a disease
phenotype of an organism. On the other hand, iron ions can
contribute, through the Fenton reaction, to the production of
reactive oxygen species (ROS), including free radicals, which
can be toxic for the cell. Iron ions are carried in the
bloodstream attached to transferrin (Tf), an 80 kDa transporter
protein, upon binding to its receptor (4). Iron homeostasis is
managed by the regulation of the expression of iron-regulatory
proteins (IRPs), which can bind iron-responsive elements (IREs)
on the mRNA of regulated proteins (5). Most non-heme iron in the
circulation is bound to transferrin, which can bind two
molecules of ferric (3+) iron with a high affinity (4). Adults
normally have approximately 3 mg of circulating non-heme iron,
with transferrin binding sites only approximately 30% saturated.
Most of the metabolically active iron in the cell is processed
in the mitochondria, which contain their own mitochondrial
ferritin (MtF), distinct from its cytoplasmatic counterpart (6).
MtF has been shown to possess ferroxidase activity and its
function is unclear. The results of some studies suggest that
MtF may protect mitochondria from iron-induced oxidative damage,
since its elevated level was observed in the mitochondria of
iron-overloaded sideroblasts in sideroblastic anemia (7).
Iron that is not utilized or stored by the cell is extruded by
ferroportin, a transport protein (8). Iron transported by
ferroportin is in ferrous state and must be oxidized to be
accepted by transferrin. This process is assisted by several
proteins, including ceruloplasmin, a copper binding protein,
containing about 95% of plasma.
As mentioned above, the interaction between IRPs and IREs is
essential for the iron homeostasis. This interaction allows the
cell to regulate iron uptake, sequestration, and export
according to their status. IRPs detect intracellular iron status
and, in the case of deficiency, bind to IREs on the mRNA of the
regulated protein. In particular, the binding of IRPs to the IRE
of ferritin, disturb the process of translation, resulting in a
decreased ferritin levels in iron deficiency. Iron is absorbed
in the intestine, but very little iron is excreted, leading to
an increase in tissue iron levels with age.
Iron ions in the retina
Retina is separated from the bloodstream by the blood-retina
barrier. Transferrin cannot diffuse trough the blood-brain
barrier and the same applies to the barrier between blood and
retina, although transferrin can be found in the retina. The
expression of transferrin mRNA was detected in RPE cells, which
could suggest that RPE is the main site of the transferrin
synthesis. Transferrin with iron can be endocytosed into cells
following binding to the cell surface transferrin receptor (9).
Transferrin receptors were detected in RPE.
Iron complexed with transferrin may be taken up by transferrin
receptors on the inner segments of photoreceptors. It was shown
that rat’s photoreceptor inner segments were immunopositive for
transferrin receptor (10). Transferrin is also present in the
aqueous and vitreous humor, which suggests that they may
constitute a route for iron delivery to ocular cells (11,12).
Some experimental data suggests that part of the transferrin can
be synthesized in the eye (13). Iron can be transported across
the blood-retina barrier by the transcytosis of Tf-bound iron
and endocytosis of Tf-bound iron followed by the removal of iron
from Tf within endosomes (14). In the same research it was
suggested that there was a mechanism regulating iron uptake by
the retina. This mechanism decreases the uptake when the retina
has sufficient amount of it.
It has been reproted that iron ions in the retina may be also
transported by divalent metal transporter-1 (DMT1), moving one
atom of ferrous iron and a proton in the same direction. DMT1
was localized in rod bipolar cell bodies, photoreceptor inner
bodies, rod bipolar cell axon termini and horizontal cell bodies
(15). Another protein which can be involved in iron transport in
the retina is Dexras1, a 30 kDa protein belonging to the Ras
subfamily. It can be induced by the activation of some receptors
to signal iron uptake in the brain (16). Iron in the cell is
primarily stored in cytoplasmic ferritin, one molecule of which
can hold about 4500 iron molecules (17). Ferritin has heavy and
light subunits and it is its central core that is responsible
for iron binding. Although ferritin is a cytoplasmatic protein,
it can be found in the nucleus of corneal epithelial cells,
where it likely sequesters iron to prevent UV-induced DNA damage
(18).
Another protein which can be involved in iron homeostasis,
ceruloplasminhas ferroxidase activity and oxidizes iron from
Fe2+ to Fe3+. This activity represents antioxidant properties of
ceruloplasmin, since this is Fe2+ which catalyzes free radicals
production via the Fenton reaction. Moreover, ceruloplasmin
facilitates iron export by the same reaction, since only ferrous
iron can be exported across the plasma membrane, but only ferric
iron can be taken up by transferrin (19).
Therefore, iron supplied with the diet and iron coming from the
environment can both be present in the retina. Moreover, it was
observed that retinal iron levels are higher in maculas from
post mortem donors aged over 65 than in those younger than 65
(20). This is consistent with the effect of iron accumulation
with age. Obviously, this iron accumulation is potentially toxic.
Iron in AMD
Results of some research suggest that iron ions may contribute
to the pathogenesis of AMD. Probably the most direct evidence
for the involvement of iron ions in the etiology of AMD arises
from the results of post-mortem research comparing the iron
content in the macula of AMD patients and sex- and age-matched
individuals without visual disturbances (21). Moreover, it was
shown in the same study that the retinas from AMD patients had
more transferrin than retinas persons without AMD. AMD patients
showed not only iron ions themselves, but also higher
concentrations of transferrin than in an age-matched control
group (22). However, the fact that the retinas of AMD patients
had more iron and transferrin than those of healthy subjects
does not indicate unambiguously that iron is the cause of AMD,
for it can be a byproduct of AMD pathology. Transferrin was
reported to be upregulated at the mRNA and protein levels in
patients with AMD compared to age-matched healthy controls (23).
Through its involvement in the Fenton reaction, iron is
implicated in the oxidative stress, which, in turn, can be
involved in the pathogenesis of AMD. Therefore, a link between
iron and AMD seems to be straigthforward. Moreover, it seems
that antioxidants and iron chelators can be beneficial in
preventing and curing AMD. But in fact, the source of oxidants,
which may play a role in the etiology of AMD, is unknown. The
thesis that iron can be this source is controversial, albeit –
in our opinion – rational.
It is remarkable that iron content in the retina increases with
age, as shown in eyes of individuals below the age of 35
compared with subjects older than 65 (22). An early onset of
macular drusen-like opacities was reported in a patient with
retinal iron overload resulting from the hereditary disease
aceruloplasminemia. Mice with the iron overload in RPE resulting
from disturbances in the iron exporter celuroplazmin developed a
retinal degeneration with some features of AMD, including
sub-RPE deposits and subretinal neovascularization (24)).
An intraocular iron overload was shown to initiate oxidative
damage to the retina induced by superoxide radicals in
photoreceptor inner segments (25). Therefore, if we assume that
oxidative damage to the retina can be a prerequisite to AMD,
iron ions can initiate a cascade of events leading to the
development of the disease.
If iron indeed plays a role in the pathogenesis of AMD, iron
chelators could be effective in protecting against the
pathological effects of iron. Moreover, if we assume that the
harmful effect of iron is carried out through oxidative stress,
similar protective effects should be manifested following
antioxidant supplementation. In fact, the results obtained in
the Age-Related Eye Disease Study have shown that substances
recognized as antioxidants: zinc, vitamin C, vitamin E and
β-carotene may slow down the progression of AMD (26).
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Concluding remarks
In the light of a very likely role of iron in the pathogenesis
of AMD it seems imperative to establish the relationship between
dietary iron and retinal iron. Until then, patients with retinal
disease, including AMD, should avoid taking iron as dietary
supplement and eating red meat, unless they are instructed to do
so due to disturbances in iron homeostasis, such as iron
deficiency anemia. It also seems important to consider the role
of iron ions in the degeneration of the retina in general, for
it can potentiate the effect of aging in AMD.
Since studies on antioxidants in AMD brought promising results,
they could inspire their expansion by using iron chelators to
modulate the occurrence and/ or progression of AMD. It is
justified by the reports suggesting that iron chelation may play
a role in the treatment of a number of neurological degenerative
diseases such as Alzheimer’s disease and Parkinson’s disease,
Huntington’s disease and others (27,28). However, from an
ophthalmologic point of view, considering iron chelation as a
therapeutic or preventive strategy against AMD must be done with
great caution, since in some cases this process may induce
retinal toxicity (29).
The research on the role of iron in AMD should also involve a
search for a correlation between markers of AMD and polymorphism
of the genes coding for proteins involved in iron transport and
storage in the retina: ferritin, ceruloplasmin, ferroprotin and
others. The results of such studies may be useful for
constructing a microarray for the assessment of the risk of AMD
occurrence and progression linked with disturbances of iron
homeostasis. More detailed study should be also directed to a
role of cerulopasmin in AMD, since it can play a pronounced role
in the iron homeostasis and exert an antioxidant effect.
In summary we can state that there is no doubts that disturbed
homeostasis of iron is associated with AMD, but the question
whether it is the reason or a result of AMD remains open.
Acknowledgement
This work was supported by the grant from the Ministry of
Science and Higher Education number 3C68.
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The study was originally received: 16.05.2008. (1049)/
Praca wpłynęła do Redakcji 16.05.2008. (1049)
Accepted for publication: 20.04.2009/
Zakwalifikowano do druku 20.04.2009 r.
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