EUKARYOTIC CELL, Jan. 2008, p. 20–27
Vol. 7, No. 1
Response to Iron Deprivation in Saccharomyces cerevisiae?
Caroline C. Philpott* and Olga Protchenko
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10,
Room 9B-16, 10 Center Drive, MSC 1800, Bethesda, Maryland 20892-1800
Iron is an essential nutrient for almost every organism be-
cause iron cofactors, such as heme and iron-sulfur clusters
(ISC), are required for the activity of numerous cellular en-
zymes involved in a wide range of cellular processes. Although
iron is a very abundant metal in the earth’s crust, it has a low
bioavailability. In aerobic environments, iron is largely present
in the oxidized, ferric form, which is poorly soluble at neutral
pH. Thus, iron can be limiting for growth, and single-celled
organisms and plants have evolved sophisticated strategies for
acquiring iron from the environment. In humans, iron is ab-
sorbed poorly from the diet, especially if the diet is entirely
plant based and low in ascorbic acid. Iron deficiency is the most
common nutritional deficiency in the world and is a significant
public health problem, especially among children and women
of childbearing age (68). The most obvious manifestation of
iron deficiency in humans is anemia, but iron deficiency has
adverse effects on the immune system and cognitive develop-
ment as well. Although the pathogenesis of anemia in iron
deficiency is well understood, other manifestations of iron de-
ficiency are not understood at the cellular or metabolic level.
Conversely, the accumulation of excess iron within cells is a
feature of several human diseases, both acquired and inher-
ited, and the mechanisms by which excess iron damages cells
are far from clear (3, 17, 35, 40). Work with the simple eu-
karyote Saccharomyces cerevisiae has begun to reveal how cells
adapt to changes in the availability of iron.
The budding yeast S. cerevisiae can thrive in environments in
which the bioavailable iron is extremely scarce or overly abun-
dant, and it can survive tremendous fluctuations in iron avail-
ability. This review focuses on the strategies exhibited by this
organism as it responds to the depletion of iron in its environ-
ment. This response consists of the following three aspects: (i)
activation of systems of iron uptake, (ii) mobilization of intra-
cellular stores of iron, and (iii) metabolic adaptations to iron
limitation. Furthermore, the response appears to be graded,
that is, lesser degrees of iron deprivation trigger a modest iron
deficiency response, while greater degrees trigger a greater
response. Much of this response is mediated through changes
in transcription, but additional, posttranscriptional mecha-
nisms are also employed.
AFT1P AND AFT2P ARE THE PRINCIPAL MEDIATORS
OF THE TRANSCRIPTIONAL RESPONSE TO IRON
The primary response to iron depletion in yeast is the tran-
scriptional activation of a set of genes under the control of the
iron-dependent transcription factor Aft1p (Fig. 1) (64, 65).
Aft1p is constitutively expressed, and when intracellular iron is
abundant, Aft1p is localized to the cytosol and does not acti-
vate transcription (66). When iron levels are low, Aft1p accu-
mulates in the nucleus, where it binds to DNA and activates
transcription. Aft1p appears to sense intracellular iron levels,
but whether Aft1p directly binds iron is not known. Aft1p is
thought to continuously cycle in and out of the nucleus. Trans-
port of Aft1p into the nucleus is dependent on the karyopherin
Pse1p and occurs through the interaction of Pse1p with two
nonclassical nuclear localization sequences within Aft1p (59).
The binding of Pse1p to these sequences is not regulated by
iron, and the effects of iron on Aft1p localization do not appear
to be exerted through nuclear import.
Elevated intracellular iron levels trigger the nuclear export of
Aft1p, and numerous cellular proteins are required for this ex-
port. A series of conserved cysteine desulfurases, scaffold pro-
teins, iron chaperones, and thioredoxins located in mitochondria
are required for the assembly of ISC prior to their insertion into
enzymes that require these cofactors. The mitochondrial ISC as-
sembly machinery is required for the iron-dependent nuclear ex-
port of Aft1p. Deletion of the mitochondrial monothiol glutare-
doxin Grx5p (1), depletion of mitochondrial frataxin (Yfh1p), or
depletion of glutathione leads to a loss of both mitochondrial ISC
assembly and iron-dependent inactivation of Aft1p (4, 52). The
mitochondrial inner membrane transporter Atm1p transports a
compound that is required for both cytosolic ISC maturation and
Aft1p inactivation, yet the cytosolic ISC machinery itself is not
required for Aft1p inactivation. Depletion of the cytosolic ISC
proteins Nar1p, Cfd1p, and Nbp35p does not induce the expres-
sion of Aft1-regulated genes and hence does not prevent the
iron-induced inactivation of Aft1p.
The nuclear monothiol glutaredoxins Grx3p and Grx4p are
required for the inactivation and nuclear export of Aft1p, and
deletion of both Grx3p and -4p results in constitutive expres-
sion of Aft1p target genes (37, 46). Both glutaredoxins can
bind to Aft1p, and a conserved cysteine residue in the glutare-
doxin active site is required for binding and inactivation. Grx3p
and -4p binding does not appear to be regulated by iron,
however, and cannot explain the iron-dependent inactivation of
Aft1p. Ueta and colleagues recently reported that the amino-
* Corresponding author. Mailing address: Liver Diseases Branch,
National Institutes of Diabetes, Digestive and Kidney Diseases, Na-
tional Institutes of Health, Building 10, Room 9B-16, 10 Center Drive,
MSC 1800, Bethesda, MD 20892-1800. Phone: (301) 435-4018. Fax:
(301) 402-0491. E-mail: firstname.lastname@example.org.
?Published ahead of print on 9 November 2007.
and carboxyl-terminal domains of Aft1p exhibit an intermolec-
ular interaction in the presence of iron and that iron induces
the formation of dimers of Aft1p (58). These interactions re-
quire cysteine residue 291 in both binding partners, and this
residue is mutated in a constitutively active allele of AFT1.
This iron-dependent interaction allows the nuclear exportin
Msn5p to bind to Aft1p and mediate its transfer to the cytosol.
These observations suggest a model in which, in the presence
of iron, dimers of Aft1p form a mixed disulfide bridge, perhaps
involving Grx3p and -4p and some product of the ISC machin-
ery. Increasing levels of cellular iron could be reflected in an
increase in the amount of the compound that is produced by
the ISC machinery and transported by Atm1p (Fig. 1). How-
ever, no direct experimental evidence is currently available to
support or refute this model.
Heme also plays a role in the transcriptional activation of
Aft1p target genes, as disruption of heme biosynthesis impairs
the transcription of a subset of these genes in response to iron
depletion (10). In the absence of heme, genes encoding the
high-affinity ferrous iron transport complex are repressed, and
this repression requires Tup1p and Hda1p (9). Other Aft1p
targets, such as the genes encoding the siderophore transporter
Arn1p and the cell wall protein Fit1p, are not repressed in the
absence of heme and require Cti6p to escape repression (9,
45). Because both heme synthesis and ferrous iron uptake (but
not siderophore uptake) are oxygen-dependent processes, this
requirement for heme may allow the cell to coordinate iron
uptake with oxygen availability. The activation of some Aft1p
target genes also depends on Tup1p (9, 28), and the global
regulators Ssn6p and Nhp6p interact with Aft1p to enhance
transcription at the FRE2 promoter (13). The mediator com-
plex is an evolutionarily conserved coregulator of RNA poly-
merase II transcription, and the modular components of the
complex can have antagonistic effects on the transcription of
specific genes. Cdk8p-mediated phosphorylation of a single
site in the tail of the mediator complex can also specifically
repress Aft1p target genes (62). Environmental factors other
than iron depletion, such as the glucose depletion that occurs
during the diauxic shift, also appear to activate Aft1p (16).
Glucose depletion triggers a transition from fermentative to
respiratory metabolism and is accompanied by increased ex-
pression of several Aft1p target genes. Both Aft1p and the
Snf1p/Snf4p kinase are required for this induction. Exposure
to toxic levels of cobalt also activates Aft1p, although the
mechanism of Aft1p activation under such conditions is not
Nuclear Aft1p recognizes and binds to consensus sequences
(PyPuCACCC) in the upstream regions of target genes (65). A
paralogue of Aft1p, termed Aft2p, is 39% identical to Aft1p,
recognizes similar consensus sequences, and can activate tran-
scription of a partially overlapping set of target genes (2, 8, 50,
51). The role of Aft2p in the response to iron depletion is much
less clear, however, as the transcriptional effects of Aft2p are
largely inapparent unless strains are deleted for Aft1p. Similar
to Aft1p, Aft2p is activated by iron depletion and directs the
transcription of many Aft1p target genes as well as two genes,
SMF3 and MRS4, that are not targets of Aft1p. Aft2p appears
to recognize a slightly different target sequence from that rec-
ognized by Aft1p. While Aft1p exhibits its strongest activation
when the target is TGCACCC, Aft2p can recognize the se-
quences GGCACCC (present in MRS4) and CGCACCC
(present in SMF3) (8, 51). The roles of these genes in vacuolar
and mitochondrial iron transport, respectively, have led some
investigators to suggest that Aft2p preferentially influences intra-
cellular iron utilization (8).
THE AFT1P REGULON: GENES OF IRON UPTAKE
Aft1p activates the transcription of a specific set of genes
involved in the acquisition of iron from the environment, the
mobilization of stored iron, and the metabolic alterations that
occur during growth under iron-limited conditions. The Aft1p
and Aft2p target genes, their subcellular locations, and their
functions are presented in Table 1 and Fig. 2 (8, 44, 51, 53).
Seventeen genes in the Aft1p regulon are involved, either
FIG. 1. Iron-dependent transcriptional regulation in Saccharomy-
ces cerevisiae. (A) Activation of Aft1p under conditions of iron depri-
vation. The nuclear importin Pse1p mediates Aft1p translocation into
the nucleus. Aft1p forms a complex with Grx3p and Grx4p, binds to
DNA, and activates transcription. Although complex formation is not
regulated by iron, it is not known whether complex formation occurs
exclusively in the nucleus or also in the cytosol. “Coregulators” repre-
sent the numerous coactivators and corepressors that contribute to the
regulation of the Aft1p regulon. These include the mediator complex,
Snf1p/Snf4p, Ssn6, Nhp6p, Tup1, Hda1p, Cti6p, and heme. (B) Reg-
ulation of Aft1 activity under iron-replete conditions. Yfh1p, Grx5p,
and glutathione are required for the production of ISC and the for-
mation of an unknown compound that is a substrate for Atm1p. This
compound is exported from mitochondria and may possibly be tar-
geted to the nucleus. Under iron-replete conditions, Aft1p forms
dimers that are recognized by the nuclear exportin Msn5p and lead to
the accumulation of Aft1p in the cytosol. In a hypothetical model for
the regulation of Aft1p, the production of the substrate for Atm1p is
proportional to cellular iron levels. This substrate accumulates in the
nucleus and leads to the dimerization of Aft1p, perhaps through the
formation of a mixed disulfide bridge, and the complex is exported
from the nucleus.
VOL. 7, 2008 MINIREVIEW21
directly or indirectly, in the uptake of iron at the plasma mem-
brane, and these genes allow S. cerevisiae to take up iron in the
variety of forms that can be present in the extracellular milieu.
S. cerevisiae takes up iron in the form of ferric and ferrous salts;
low-affinity iron chelates, such as ferric citrate; and high-affinity
iron chelates, such as ferric siderophores. Siderophores are a
heterogeneous class of low-molecular-weight organic com-
pounds that bind ferric iron with exceptionally high affinities
and specificities (36). They are synthesized and secreted in the
iron-free form by most species of bacteria and fungi. Extracel-
lular siderophores can bind and thereby solubilize ferric iron,
and the iron-siderophore complex can then be captured by
cellular transport systems. Although S. cerevisiae does not syn-
thesize siderophores, it can take up iron bound to a variety of
Before iron can be taken up by the yeast cell, it must first
traverse the cell wall. The Aft1p regulon includes a family of
three cell wall mannoproteins that are transcribed at very high
levels during iron depletion, and these are termed Fit1p, Fit2p,
and Fit3p (42). These proteins contribute to the retention of
the siderophore ferrichrome in the cell wall and enhance the
uptake of iron bound to ferrichrome and ferrioxamine B. The
mechanism by which the FIT genes enhance uptake is not
known, but it may involve facilitating the passage of bulky
iron-siderophore chelates through the cell wall or increasing
the concentration of siderophores in the periplasmic space.
UPTAKE OF IRON AT THE CELL SURFACE BY THE
S. cerevisiae expresses two genetically separate systems for
iron uptake, namely, a reductive system and a nonreductive
system. Ferric salts and ferric chelates are substrates for the
reductive system, while the nonreductive system exclusively
recognizes siderophore-iron chelates.
Reductive uptake is a two-step process in which ferric iron is
first reduced to the ferrous state and then the ferrous iron is
transported into the cytosol via a high-affinity, ferrous-specific
transport complex. This system of uptake has been reviewed in
detail (24, 39, 63). Briefly, the reduction step is catalyzed by
members of the FRE family of metalloreductase genes. FRE1
and FRE2 encode flavocytochromes that comprise the ma-
jority of surface reductase activity. They are required for
growth on media that contain low concentrations of ferric
iron salts, and they can catalyze the reductive release of iron
from a variety of siderophores. Because reduced iron has a
low affinity for siderophore ligands, reduction of ferric-sid-
erophore complexes results in the release of ferrous iron,
which can be taken up by the ferrous-specific transporter.
FRE3 encodes a plasma membrane reductase that can cat-
alyze the reductive uptake of iron bound to hydroxamate
siderophores, and Fre4p can catalyze uptake from dihydrox-
amate rhodotorulic acid. Each of these reductases is in-
TABLE 1. Aft1p/Aft2p target genes and the subcellular locations and functions of their products
Functional category and open reading frame Gene nameLocation Function
Uptake of iron at the cell surface
Endosome, plasma membrane
Endosome, plasma membrane
Multicopper oxidase, Fe(II) uptake
Permease, Fe(II) uptake
Cu chaperone, delivers Cu to Ccc2p
Cu transport into vesicles
Hydroxamate siderophore transport
Efflux of iron from vacuole to cytosol
Multicopper oxidase, Fe(II) transport
Permease, Fe(II) transport
Zn and Co storage/detoxification
Mitochondrial iron import
Metabolic adaptation to low iron
aPredominantly regulated by Aft2p. All others are predominantly regulated by Aft1p.
bTAFC, triacetylfusarinine C.
22 MINIREVIEWEUKARYOT. CELL
duced by Aft1p under conditions of iron depletion, while
FRE1 is also induced by copper depletion via Mac1p. Two
additional FRE family members, FRE5 and FRE6, are also
under the control of Aft1p, and Fre6p has been shown to
localize to the vacuole, where it functions in the reductive
transport of iron and copper from the vacuole to the cytosol
(49, 54). A seventh member, FRE7, is under the control of
the copper-dependent Mac1p transcription factor.
Copper has an important role in reductive iron uptake,
and Aft1p induces the transcription of four genes with links
to copper. Reduced iron is taken up through a high-affinity
transport complex that consists of a multicopper ferroxidase
(Fet3p) and a permease (Ftr1p). The oxidase activity of
Fet3p is required for iron uptake, and copper is required for
the oxidase activity of Fet3p. Copper is inserted posttrans-
lationally into Fet3p in a post-Golgi compartment of the
secretory pathway, and the copper chaperone Atx1p and the
post-Golgi copper transporter Ccc2p are required for cop-
per insertion. Atx1p and Ccc2p are regulated by iron, not
copper, which suggests that they function primarily in iron
uptake rather than copper homeostasis. Molecular oxygen is
also required for the activity of Fet3p, and under hypoxic
conditions, cells express a low-affinity ferrous iron trans-
porter, Fet4p, that serves as an oxygen-independent system
of iron uptake (15, 19). A paralogue of Fet3p, termed Fet5p,
assembles with a paralogue of Ftr1p, termed Fth1p, to form
a ferrous iron transport complex (55, 61) that functions in
conjunction with Fre6p at the vacuolar membrane (49, 54).
Although FET5 does not appear to be regulated directly by
Aft1p, the remainder of these genes are regulated by iron
NONREDUCTIVE UPTAKE OF IRON BY
S. cerevisiae can take up a variety of siderophore-iron che-
lates through a homologous group of transporters that com-
prise the ARN/SIT subfamily of the major facilitator super-
family of transporters (reviewed in reference 39). Each of
these transporters is predicted to have 14 transmembrane do-
mains and to transport intact iron-siderophore chelates. Each
transporter exhibits specificity for a group of fungal and/or
bacterial siderophores, and some strain-dependent differences
in specificity have been described (Table 2). Some of the sid-
erophore transporters are regulated posttranslationally by
their localization within the late secretory pathway. Both
Arn1p and Arn3p/Sit1p traffic directly from the trans-Golgi
network to the vacuole for degradation when their respective
siderophore substrates are not present extracellularly (14, 23).
Arn1p is recognized at the trans-Golgi network by Gga2p, a
FIG. 2. Response to iron deprivation in Saccharomyces cerevisiae. Proteins under the transcriptional control of Aft1p and Aft2p are labeled with
black text. Ccc1p, proteins of the tricarboxylic acid cycle, the respiratory cytochromes, and the glutamate, heme, and biotin biosynthetic pathways
are down-regulated during iron deficiency and are indicated with gray text.
TABLE 2. Siderophore substrates of ARN/SIT family of
Transporter Siderophore substrateKtb(?M)
aFerrichromes include ferrichrome, ferrichrome A, ferricrocin, ferrichrycin,
ferrirhodin, and ferrirubin. Some strain-specific variation in the specificities of
Arn1 and Arn3 for different ferrichromes has been reported (18, 28, 67).
bKt, equilibrium transport constant.
VOL. 7, 2008MINIREVIEW 23
clathrin adaptor protein, which directs the transporter to the
vacuolar protein sorting pathway (21). Arn1p is then ubiquitin-
ated by Rsp5p and sorted into the multivesicular body for
delivery to the vacuolar lumen. Both Arn1p and Arn3p/Sit1p
are diverted from the vacuolar sorting pathway to the plasma
membrane in the presence of their respective siderophore sub-
strates, and in the case of Arn1p, this relocalization involves
the binding of ferrichrome to a receptor domain of the Arn1p
transporter itself (14, 22). In contrast, Arn4p/Enb1p traffics
directly to the cell surface, even in the absence of its substrate,
enterobactin. The relocalization of Arn1p and Arn3p/Sit1p to
the plasma membrane only in the presence of their specific
siderophore substrates effectively prevents these transporters
from moving nonspecific substrates across the plasma mem-
brane when the specific substrate is unavailable. Thus, the cell
is protected from the uptake of potentially toxic small mole-
cules. Why does Arn4p/Enb1p not traffic in this pattern? En-
terobactin is structurally very dissimilar from the hydroxamate
siderophores ferrichrome and ferrioxamine B; perhaps S. cer-
evisiae is exposed to a toxic small molecule that structurally
mimics the hydroxamates but not enterobactin and thus the
trafficking of Arn1p and Arn3p/Sit1p protects the cell from this
Higher levels of extracellular ferrichrome are associated
with both the uptake of ferrichrome and the cycling of Arn1p
on and off the plasma membrane (23). Both ubiquitination via
Rsp5p and the activity of Gga1p and -2p (C. C. Philpott and Y.
Deng, unpublished observations) are involved in the internal-
ization of Arn1p. Although mutations that inhibit actin-depen-
dent endocytosis and the cycling of Arn1p also inhibit the
uptake of ferrichrome, mutations in Gga2p and Rsp5, which
inhibit cycling of Arn1p and Arn3p without interfering with the
endocytosis machinery, do not inhibit uptake of siderophores,
indicating that cycling is not required for uptake (14, 21). The
internalization of the transporters to a sorting compartment
such as the early endosome may allow the cell to selectively
recycle the transporters to the plasma membrane for continued
uptake or divert them to the late endosomal pathway for vac-
Ferric siderophores are taken up as intact chelates by the ARN
transporters, but the iron must dissociate from the siderophore
prior to its use by the cell. After uptake through Arn3/Sit1p,
intracellular ferrioxamine B accumulates in the vacuole as an
intact chelate (14). Whether the iron dissociates from the sid-
erophore within the vacuole or the chelate is transported to the
cytosol prior to dissociation is not known. Ferrichrome accumu-
lates as an intact chelate in the cytosol after uptake, indicating
that both siderophores can serve as iron storage molecules (34).
Iron can be released from cytosolic ferrichrome through the deg-
radation of the siderophore. Although reductive mechanisms for
iron release from siderophores have been identified in pro-
karyotes and evidence for their existence is present in some spe-
cies of fungi, no reductive mechanism has been identified in S.
THE AFT1P AND AFT2P REGULON: MOBILIZATION OF
Yeast cells can grow in iron-depleted media for several gen-
erations, indicating that they express efficient systems for iron
storage and mobilization. S. cerevisiae and other yeast species
do not express ferritin, the major iron storage protein found in
prokaryotes and most eukaryotes. Early studies on the distri-
bution of iron in yeast reported that the vacuole is the main
iron storage compartment, although some iron is present in the
cytosol, mitochondria, and other compartments (47). When
iron is abundant in the environment, vacuoles accumulate iron
through the activity of the iron and manganese transporter
Ccc1p (5, 26). Sequestration of iron within the vacuole protects
cells from the toxic effects of iron and allows cells to utilize
stored iron when extracellular iron is scarce (29). Strains de-
leted for CCC1 cannot maintain proper iron balance and are
more sensitive to extremely high and low concentrations of
extracellular iron. Although iron-bound ferrioxamine B can
accumulate in the vacuole, the molecular form of other iron
species deposited in this compartment is less clear. Iron may
form complexes with polyphosphates or organic acids present
in the vacuole, but this awaits further research.
When extracellular iron levels fall, CCC1 transcription is
shut off, and Aft1p directs the expression of vacuolar proteins
that permit the efflux of iron from the vacuole to the cytosol to
alleviate iron deficiency. In many ways, these vacuolar proteins
duplicate the iron transport systems that are present at the
plasma membrane. One member of the FRE family of metal-
loreductases, Fre6p, is expressed exclusively on the vacuolar
membrane, where it is involved in the reduction of vacuolar
iron and copper prior to transport into the cytosol (49, 54).
Paralogues of the plasma membrane high-affinity ferrous iron
transport complex are also present on the vacuolar membrane
and are expressed under conditions of iron deficiency. Fet5p
and Fth1p are assembled into a complex that is thought to
function similarly to the Fet3p-Ftr1p complex (61). Cells lack-
ing Fet5p and Fth1p exhibit activation of the iron deficiency
transcriptional program and an impaired transition from fer-
mentation to respiration, a metabolic state that requires more
iron. Cells overexpressing Ccc1p accumulate less iron in the
vacuole when Fet5p and Fth1p are also overexpressed (54).
iron out of the vacuole (54). Smf3p is a member of the Nramp
family of divalent metal transporters, which includes the mam-
malian iron transporter DMT1. Smf3p is a paralogue of Smf1p
and Smf2p. Although Smf1p and -2p function primarily in the
uptake of manganese (41), Smf1p is also involved in the transport
of ferrous iron at the plasma membrane (6). Smf3p is the only
Nramp family member in yeast that is regulated by iron, and it is
primarily regulated by Aft2p rather than Aft1p (8, 51). Strains
lacking Smf3p exhibit activation of Aft1p target genes and accu-
mulate more iron in the vacuole (54). In contrast, overexpression
of Smf3p leads to diminished retention of iron in the vacuole.
Smf3p is also induced under conditions of oxygen deficiency and
provides the cell with an oxygen-independent mechanism for mo-
bilizing iron stored in the vacuole.
Iron-deficient cells are sensitive to the toxic effects of other
transition metals, such as cobalt, copper, zinc, and manganese,
and increased uptake of these metals through low-affinity and
low-specificity transporters may contribute to this sensitivity. Iron
depletion also triggers the Aft1p-dependent expression of Cot1p
(53), a transporter on the vacuolar membrane with specificity for
accumulation of zinc and cobalt (7, 31), and its expression during
24 MINIREVIEWEUKARYOT. CELL
iron deficiency suggests that sequestration of other metals in the
vacuole is an adaptive response (30).
In addition to the vacuolar iron storage pool, cellular iron is
also present in substantial quantities in the mitochondria, the
site of iron incorporation into heme and ISC. As such, ISC and
heme proteins constitute a cellular iron pool that can poten-
tially be mobilized for use during iron deficiency. HMX1 en-
codes the yeast heme oxygenase and is actively transcribed
during iron deficiency (20, 43). Hmx1p is a heme-degrading
enzyme localized to the cytosolic face of the endoplasmic re-
ticulum, and cells lacking Hmx1p exhibit accumulation of in-
tracellular heme, activation of Aft1p, and a reduced capacity to
utilize heme as the sole source of nutritional iron. Heme is an
important regulatory molecule in yeast and serves as an acti-
vator of the Hap1p and Hap2p/3p/4p/5p transcription factors,
which control the activation of genes involved in aerobic
growth (25). Many of these genes encode components of the
respiratory cytochromes, which are very iron-rich. Expression
of Hmx1p during iron deficiency leads to degradation of reg-
ulatory pools of cellular heme, which leads to reduced Hap1p
activation and reduced expression of iron-containing respira-
tory complexes. Thus, Hmx1p serves a dual purpose in making
heme iron available for metabolic needs and decreasing the
flux of iron into respiratory complexes.
METABOLIC RESPONSE TO IRON DEPLETION
Examination of the transcriptional response to iron deple-
tion suggests that yeast cells respond to iron depletion by
altering their utilization of iron, shifting it away from nones-
sential metabolic pathways while preserving essential ones.
Several lines of evidence support this hypothesis. S. cerevisiae can
metabolize the products of glycolysis through either fermentation
or respiration; however, strains grown in iron-depleted media or
grow on nonfermentable carbon sources. DNA microarray anal-
ysis of yeast cells grown under conditions of iron starvation versus
iron excess reveals that mRNA levels for many proteins in met-
abolic pathways that contain heme-proteins and ISC proteins are
decreased in iron-depleted cells (44, 53). These pathways include
the tricarboxylic acid cycle, the mitochondrial respiration and
electron transport chain, and the heme and biotin biosynthetic
pathways. Transcripts coding for iron-sulfur proteins involved in
the synthesis of leucine, glutamate, and lipoic acid are also dimin-
ished. Multiple mechanisms are involved in the down-regulation
of these pathways.
Cth2p/Tis11p is an Aft1p target that is strongly induced by
iron deficiency and mediates many of the changes in transcript
levels observed during iron deficiency (44). Cth2p and its para-
logue Cth1p are members of the tristetraprolin family of RNA
binding proteins and recognize AU-rich elements in the 3?
untranslated region (3?-UTR) of specific mRNA transcripts.
Binding of Cth2p to these AU-rich elements leads to destabi-
lization and degradation of the transcripts. Many of the tran-
scripts that are decreased under iron deficiency contain these
AU-rich elements and show elevated levels in a strain lacking
Cth2p. Cth2p has been shown to specifically bind to the AU-
rich element present in the 3?-UTRs of SDH4 and ACO1
mRNAs, which encode the heme-binding subunit of succinate
dehydrogenase and the ISC enzyme aconitase, respectively.
Thus, the set of genes activated by Aft1p during iron deficiency
includes a protein that specifically down-regulates transcripts
involved in the utilization of iron. This allows the cells to divert
iron that would ordinarily be incorporated into these pathways
to other, essential pathways. For example, nine genes of the
ergosterol and fatty acid biosynthetic pathways are up-regu-
lated during iron deficiency. Since both of these essential path-
ways contain iron-dependent enzymes, increased expression
during iron deficiency may represent a homeostatic mechanism
triggered by a decrease in the flux through these pathways.
Another example of the shift to iron-independent metabo-
lism in the setting of iron deficiency is illustrated by the regu-
lation of biotin acquisition. Although technically auxotrophic for
biotin, S. cerevisiae can synthesize biotin from 7-keto, 8-amino-,
and 7,8-diamino-pelargonic acid precursors and from desthiobi-
otin (38). The ultimate step in biotin biosynthesis is catalyzed by
Bio2p, an ISC protein (60). The biotin biosynthetic enzymes
Bio3p, Bio4p, and Bio2p are expressed in cells grown in iron-
replete medium but are shut off at the transcriptional level
under conditions of iron deficiency (53). Iron deficiency also
triggers the expression of the Aft1p target gene VHT1, which
encodes the transporter required for high-affinity biotin uptake
at the cell surface (57). Cells lacking Vht1p can survive by
synthesizing biotin de novo when cells have adequate levels of
iron, but they cannot synthesize sufficient biotin to support
growth under conditions of iron deficiency. Thus, yeast cells
reciprocally regulate biotin uptake and biosynthesis, relying
exclusively on uptake when iron is limited and shifting to syn-
thesis only when iron is plentiful. The transcription of the
specific transporter for the pelargonic acid precursors, Bio5p,
is also increased under conditions of iron deficiency (1), which
may indicate that cells can store biotin precursors for later
Nitrogen assimilation pathways also appear to be altered in
response to changing iron availability. Several genes involved
in amino acid and nitrogen uptake and metabolism are up-
regulated under conditions of iron deprivation, and this up-
regulation may be due to changes in glutamate synthesis during
iron deficiency (53). All of the nitrogen-containing compounds
in yeast are synthesized from the amino acids glutamate and, to
a lesser extent, glutamine, and yeast cells have two pathways
for synthesizing glutamate from ammonium, the preferred ni-
trogen source (32). Glutamate is synthesized directly from
ammonium and 2-oxoglutarate in a reaction that requires
NADPH. Two isoforms of glutamate dehydrogenase, Gdh1p
and Gdh3p, catalyze this reaction. A second pathway involves
a two-step process in which glutamine synthetase (Gln1p) cat-
alyzes the formation of glutamine from ammonium and gluta-
mate and then glutamate synthase (Glt1p) catalyzes the for-
mation of two glutamate molecules from glutamine and
2-oxoglutarate. The summation of the second, two-step path-
way is identical to the first, except that ATP and NADH are
consumed rather than NADPH. Glt1p is an ISC enzyme (33),
and both glutamate synthase activity and GLT1 mRNA levels
decrease in the setting of iron deprivation. Thus, cells shift to
an iron-independent pathway for glutamate synthesis under
conditions of iron deficiency.
The genes required for purine biosynthesis are also down-
regulated during iron deficiency, and although purine biosynthe-
sis is an iron-dependent process in most organisms, there are no
VOL. 7, 2008 MINIREVIEW25
known iron-dependent enzymes in this pathway in S. cerevisiae
(53). Expression of the purine biosynthetic pathway is regulated
homeostatically through the production of ADP and ATP, allo-
steric inhibitors of Ade4p, and by the transcription factors Bas1p
and Pho2p, which are activated by intermediates of the biosyn-
thetic pathway (11, 48). Iron appears to exert its effects upstream
of Bas1p and Pho2p, but mechanistically, the effects of iron de-
privation on purine biosynthesis remain unclear.
REVERSAL OF THE IRON DEFICIENCY RESPONSE
Expression of the genes involved in the response to iron
deficiency serves to maintain cellular iron homeostasis and to
optimize the metabolism of iron-deficient cells. Less is known
S. cerevisiae has the capacity to quickly reverse the iron deficiency
response when cells become iron replete. Aft1p is quickly inacti-
vated in iron-replete cells, and levels of FET3 mRNA are unde-
tectable within 30 min of adding iron (C. C. Philpott, unpublished
observations). Rnt1p contributes to the rapid degradation of
mRNA transcripts encoded by Aft1p-regulated genes. Rnt1p is a
double-stranded RNA endonuclease of the RNase III family.
Cells lacking Rnt1p are sensitive to iron and exhibit inappropri-
ately elevated levels of Aft1p target mRNAs under iron-replete
conditions (27). Aft1p target proteins are also regulated post-
translationally. High levels of ferrous iron uptake at the cell sur-
face lead to internalization and degradation of the Fet3p/Ftr1p
transporter complex, which tend to limit the amount of iron taken
up when cells encounter an iron-rich environment (12). Arn1p,
the ferrichrome transporter, does not exhibit a similar sid-
erophore-mediated degradation. This stability in the setting of
ferrichrome accumulation may be due to the capacity of fer-
richrome to serve as an intracellular iron storage molecule.
Studies with yeast indicate that in the face of limitation in
iron availability, cells not only will increase their uptake of iron
and their mobilization of stored iron but also will adjust their
metabolism to more efficiently use the iron that is available.
The remarkable flexibility in the use of this essential nutrient
reveals a metabolic hierarchy within the cell, with iron shifting
away from nonessential pathways and into more essential ones.
The picture of how cells respond to changes in iron is not
completely clear, however. The molecular form of iron that is
sensed by the cell and how that sensing results in altered
Aft1p/2p activity remain unclear. Although several proteins
involved in general transcriptional repression and activation
influence the expression of Aft1p target genes, we do not yet
understand the role of chromatin remodeling in the transcrip-
tional response to iron deficiency and how chromatin remod-
eling and the activity of specific transcription factors are coor-
dinated. Iron triggers the Aft1p-independent activation of
some genes, and the specific transcription factors involved in
this activation have yet to be identified.
Many of the studies described here have focused on changes
in the levels of transcripts and proteins involved in iron ho-
meostasis and the response to iron deficiency. Yet alterations
in protein levels do not always result in the predicted changes
in transport activity or flux through a metabolic pathway. De-
spite increased expression of reductases and the high-affinity
iron transport complex during growth in iron-poor media, cells
accumulate less iron in this setting. Similarly, subtle changes in
the expression of iron-containing enzymes may lead to signif-
icantly more or less iron being devoted to a particular enzy-
matic pathway, but the flux of metabolites through this enzy-
matic pathway may change little, if at all, as flux is determined
primarily by enzyme kinetics and the concentrations of en-
zyme substrates. Although the flux of metabolic intermediates
through the respiratory chain in iron-deficient cells is not suf-
ficient to support the growth of cells, it is not clear that this
phenomenon is fully explained by changes in levels of the
respiratory complexes. The extent to which flux through met-
abolic pathways and the products of biosynthetic pathways are
maintained or altered in the face of falling iron availability will
be revealed by studies of metabolite levels and the extent to
which homeostasis is achieved in iron-deficient cells. Exami-
nation of the yeast response to iron deficiency will also yield
clues as to how other organisms might prioritize their use of
iron at the cellular level.
We are supported by the intramural research program of the Na-
tional Institute of Diabetes and Digestive and Kidney Diseases of the
National Institutes of Health.
We dedicate this article to the memory of Yuko Yamaguchi-Iwai
(1960–2007). Yamaguchi-Iwai was an excellent scientist, a good col-
league, and an important contributor to the studies reviewed here.
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