Báo cáo khoa học: Sugar signalling and antioxidant network connections in plant cells pptx

REVIEW ARTICLE
Sugar signalling and antioxidant network connections in
plant cells
Mohammad Reza Bolouri-Moghaddam
1
, Katrien Le Roy
2
, Li Xiang
2
, Filip Rolland
3
and
Wim Van den Ende
2
1 Department of Agronomy, Plant Breeding and Biotechnology, Faculty of Crop Science, Sari Agricultural Science and Natural Resources
University, Iran
2 Laboratorium voor Moleculaire Plantenfysiologie, Katholieke Universiteit Leuven, Belgium
3 Laboratorium voor Functionele Biologie, Katholieke Universiteit Leuven, Belgium
Introduction
The ability of cells to perceive and correctly respond
to their microenvironment forms the basis of cellular
signalling. Glucose is an important cellular nutrient
that also acts as a regulatory metabolite modulating
gene expression in yeast, animals and plants. In plants,
sugars play important roles as both nutrients and sig-
nal molecules. Both glucose and sucrose are recognized
as pivotal integrating regulatory molecules that control
gene expression related to plant metabolism, stress
resistance, growth and development [1–3]. There is
great interest in dissecting the processes that are
involved in the sugar sensing and response pathways

allowing plants to adapt to the constantly changing
environment, but the sugars’ dual function as nutrients
and signalling molecules significantly complicates anal-
yses of the mechanisms involved [4]. Although our
knowledge of the detailed molecular mechanisms of
sugar perception and signalling in plants is far from
complete, hexokinase (HXK) and Snf1-related kinase 1
have already been identified as conserved sugar signal-
ling components controlling eukaryotic energy homeo-
stasis, stress resistance, survival and longevity.
Keywords
antioxidant; fructan; hexokinase; invertase;
mitochondria; phenolic compounds, ROS
scavenging; senescence; signalling; sugar
Correspondence
W. Van den Ende, Laboratorium voor
Moleculaire Plantenfysiologie, Katholieke
Universiteit Leuven, Kasteelpark Arenberg
31, bus 2434, B-3001 Leuven, Belgium
Fax: +32 161967
Tel: +32 16321952
E-mail:
(Received 5 January 2010, revised 15
February 2010, accepted 2 March 2010)
doi:10.1111/j.1742-4658.2010.07633.x
Sugars play important roles as both nutrients and regulatory molecules
throughout plant life. Sugar metabolism and signalling function in an intri-
cate network with numerous hormones and reactive oxygen species (ROS)
production, signalling and scavenging systems. Although hexokinase is well
known to fulfil a crucial role in glucose sensing processes, a scenario is

emerging in which the catalytic activity of mitochondria-associated hexoki-
nase regulates glucose-6-phosphate and ROS levels, stimulating antioxidant
defence mechanisms and the synthesis of phenolic compounds. As a new
concept, it can be hypothesized that the synergistic interaction of sugars
(or sugar-like compounds) and phenolic compounds forms part of an inte-
grated redox system, quenching ROS and contributing to stress tolerance,
especially in tissues or organelles with high soluble sugar concentrations.
Abbreviations
ABA, abscisic acid; ASC, ascorbic acid; AtHXK1, Arabidopsis thaliana hexokinase 1; GSH, glutathione; HXK, hexokinase; NDP-sugar,
nucleoside diphosphate-sugar; MeJa, methyl jasmonate; mtHXK, mitochondrial hexokinase; PCD, programmed cell death; RFO, raffinose
family oligosaccharides; ROS, reactive oxygen species; VHA-B1, one of three isoforms of the B subunit of the peripheral V1 complex in
vacuolar-type H-ATPase.
2022 FEBS Journal 277 (2010) 2022–2037 ª 2010 The Authors Journal compilation ª 2010 FEBS
Furthermore, invertase-related sugar signals seem to be
very important during plant defence reactions [5,6].
In conclusion, sugar signals integrate numerous
environmental and endogenous developmental and
metabolic cues and therefore operate in a complex net-
work with plant-specific hormone signalling and stress-
related pathways.
The field of antioxidants has received much atten-
tion lately, both in fundamental and applied research,
but especially in the field of medicine (food supple-
ments). Because the toxic oxygen gas appeared in the
Earth’s atmosphere 2.2 billion years ago, aerobic
organisms such as animals and plants only survived
because they evolved antioxidant defence processes [7].
The need for oxygen for the efficient production of
energy (ATP) in mitochondria is in balance with the
necessity of controlling the level of reactive oxygen

species (ROS), such as the hydroxyl radical
•
OH; the
superoxide radical O
2
•)
and hydrogen peroxide H
2
O
2
,
which are always produced in the presence of oxygen
and particularly under stress. In general, metabolic
rates appear to inversely correlate with stress resis-
tance and lifespan in a variety of organisms and this
has been attributed to oxidative stress [8], a deleterious
process caused by the overproduction of ROS that can
be important as a mediator of cell damage leading to
various disease states, senescence and aging in
humans, animals [9] and plants [7]. In plants, high
photosynthetic activity in source leaves can induce the
accumulation of both soluble sugars and ROS.
Intriguingly, however, sugar starvation can lead to
ROS accumulation as well [10]. Enzymic and nonenzy-
mic antioxidants as endogenous protective mechanisms
work in a complex co-operative network to reduce the
cytotoxic effects of ROS in both plant and animal cells
[11–13].
Increased cellular oxidation is also a key feature of
leaf senescence [14], a process that seems to be associ-

ated with temporal high levels of soluble sugars.
Although an involvement of metabolic signals in the
regulation of plant senescence has been demonstrated
in a range of studies [15, and references therein], the
exact mechanisms involved in the stimulation of the
ROS detoxification systems remain largely unresolved.
So far, the protective effects of soluble sugars against
oxidative stress have been mostly attributed to (indi-
rect) signalling effects, triggering the production of
specific ROS scavengers [10,16]. However, it was
recently proposed that soluble sugars, especially when
they are present at higher concentrations, might act as
ROS scavengers themselves [17]. Here, the putative
roles of sugars and sugar metabolizing enzymes in
both sugar and ROS signalling pathways and their
co-operation with antioxidant networks in plant cells
are presented. A picture is emerging in which the activ-
ity of HXK may control ROS production in plant
organelles such as mitochondria and chloroplasts.
Also, the effect of these pathways on plant senescence
is discussed.
Sugar signalling, a multifunctional
network
Sugars not only fuel growth and development as car-
bon and energy sources, but in addition have acquired
important regulatory roles as signalling molecules [2,3].
This is now particularly well established for glucose,
the prime carbon and energy source in eukaryotic cel-
lular metabolism. HXK, the first enzyme in glucose
catabolism, was identified as a genuine glucose sensor,

with separable catalytic and signalling activities [18,19]
(Fig. 1). In addition, HXK-independent glucose and
sucrose signalling pathways appear to be active in
plants [20–24], but a sucrose sensor remains to be iden-
tified (Fig. 1). Although glucose signalling has been
associated primarily with active cell division, respira-
tion, cell wall biosynthesis and sugar-mediated feed-
back regulation of photosynthesis (Fig. 1), sucrose
signalling appears to be specifically associated with
anthocyanin production and with the regulation of
storage- and differentiation-related processes [24–26]
(Fig. 1). In addition to the important post-transla-
tional effects on metabolic enzyme activity, genome-
wide expression profiling has recently uncovered the
huge impact of carbon status on gene expression [27–
32]. Diverse environmental stress conditions can cause
cellular energy starvation, triggering metabolic repro-
gramming through the Snf1-related kinase 1 pathway
[33 and references therein].
Excess photosynthate is generally transiently stored
as starch in the chloroplast during the day, in part
through sugar-mediated induction of gene expression
and redox activation of ADP-glucose pyrophosphory-
lase, a key enzyme in starch biosynthesis [34–36].
Apart from the breakdown of sucrose by invertases
(see below), the degradation of chloroplastic starch in
leaf cells during the night (mainly via maltose and
glucose export) and from plastids (amyloplasts) in
starch-storing organs is also a putative source for
glucose signals [25,37]. Also, trehalose metabolism

appears to play an important regulatory role in
co-ordinating metabolism with plant growth and
development [38]. Apart from the breakdown of
sucrose and reserve carbohydrates, the hydrolysis of
cell wall polysaccharides might also generate sugar
signals. Several cell wall glycoside hydrolases are
M. R. Bolouri-Moghaddam et al. Sugar signalling and antioxidant networks in plants
FEBS Journal 277 (2010) 2022–2037 ª 2010 The Authors Journal compilation ª 2010 FEBS 2023
upregulated under stress conditions such as darkness,
sugar depletion, senescence and infection [33,39,40].
The exact molecular mechanisms involved in sugar
signalling are still largely unknown, but mutant
screens have revealed a tight interaction with various
hormone signalling pathways [2]. Glucose controls
abscisic acid (ABA) signalling and biosynthesis gene
expression [41] and HXK-dependent signalling inter-
acts positively and negatively with auxin and cytoki-
nin signalling, respectively [19]. Glucose and ethylene
signalling converge at the level of EIN3 protein stabil-
ity [42].
Role of sucrose splitting enzymes
Sucrose is one of the most widespread disaccharides in
nature. In higher plants it represents the major trans-
port compound bringing carbon skeletons from source
(photosynthetically active leaves) to sink tissues (roots,
young leaves, flowers, seeds, etc.). Invertases mediate
the hydrolytic cleavage of sucrose into glucose and
fructose (Fig. 1). These enzymes are very well studied
in plants, fungi and bacteria. For a long time, inverta-
ses were believed to be absent in the animal kingdom.

Recently, however, at least two invertases have been
discovered in the genome of Bombyx mori, but their
exact functions remain unclear [43].
Plants possess three types of invertase: acid cell wall
invertases (glycoside hydrolase family 32) located in
the apoplast (i.e. the continuum of cell walls of adja-
cent plant cells), acid vacuolar invertases (glycoside
hydrolase family 32) located in the vacuole and neu-
tral ⁄ alkaline invertases (glycoside hydrolase family
100) located in the cytoplasm, chloroplasts and mito-
chondria [44–47]. Neutral invertases can be inhibited
by glucose and fructose [48,49]. Knock outs of two
cytoplasmic neutral invertases in Arabidopsis [50] and
the model legume Lotus japonicus [51] resulted in
severely reduced growth rates. It remains to be further
explored whether the invertase exerts a direct effect on
plant growth and development or an indirect effect via
glucose signalling (Fig. 1). Intriguingly, the nuclear
Fig. 1. A hypothetical sugar–antioxidant network in plant cells. Glucose (Glc) and the activity of (organellar) HXK take a central position in this
scheme, as they emerge as important regulators of cytosolic ROS. The HXK generated glucose-6-phosphate (Glc6P) and NDP-glucose boost
the glycosylation of phenolic compounds, the synthesis of ASC and contribute to hormone homeostasis. The released ROS is used as a signal
to stimulate the antioxidant defence system. In parallel with HXK activity, HXK acts as a glucose sensor, controlling cell division and cell
expansion, in concert with hormone and ROS signalling. Next to glucose, sucrose can also be sensed and metabolized. Invertases (INVs) can
influence plant growth and development either directly (e.g. by influencing source–sink relationships or by acting as a true regulatory protein)
or indirectly via sugar signalling (altering the hexose ⁄ sucrose ratio). Sucrose is sensed by an unknown sensor stimulating the accumulation of
reserve compounds (e.g. vacuolar fructan biosynthesis) and anthocyanins. Both anthocyanins and phenolic compounds might be involved in
the scavenging of cytosolic ROS, creating phenolic compound radicals (phenolic compounds
•
), which are reduced by ASC. It is postulated that
sugars at high concentrations (sucrose, fructans, sugar-like compounds) could directly scavenge ROS derived from excess H

2
O
2
entering the
vacuole, producing sugar radicals (sugar
•
). Vacuolar glycosylated phenolic compounds might assist in recycling the sugars from sugar radicals.
Sugar signalling and antioxidant networks in plants M. R. Bolouri-Moghaddam et al.
2024 FEBS Journal 277 (2010) 2022–2037 ª 2010 The Authors Journal compilation ª 2010 FEBS
localization of AtCINV1, a well-characterized neutral
invertase of Arabidopsis, and its interaction with
a phosphatidylinositol monophosphate 5-kinase [52]
strongly suggest that (at least some) neutral invertases
can fulfil regulatory functions apart from their cata-
lytic function [53]. It is becoming increasingly clear
that invertases can do much more than simply hydro-
lyse sucrose. For instance, the LIN6 cell wall invertase
of tomato is considered to be a pivotal enzyme for the
integration of metabolic, hormonal and stress signals,
regulated by a diurnal rhythm [54]. Expression of a
yeast-derived invertase in the apoplast under a meri-
stem-specific promoter caused accelerated flowering
and enhanced branching of the inflorescence and seed
yield, whereas a cytoplasmic localization of this invert-
ase resulted in delayed flowering and both reduced seed
yield and branching in Arabidopsis [55]. In potato, cyto-
plasmic localization of yeast invertase was detrimental
to tuber yield, whereas the opposite was observed for
an apoplastic yeast invertase construct [56]. Targeting
of this yeast invertase to plastids resulted in early leaf

senescence, consistent with reduced sucrose and
increased hexose levels in the leaves [57]. These results
emphasize the importance of the exact source, nature
and location of the sugar signals [55] and the impor-
tance of invertases as modulators of the sucrose ⁄
glucose ratio. The sucrose ⁄ glucose ratio might be more
important than the absolute sucrose and glucose con-
centrations, as suggested by different groups [58–63],
but this requires further investigation.
Biotic or abiotic stresses and hormonal signals can
also induce cell wall invertase expression and sink for-
mation in leaf tissues [45]. Sucrose synthase is also able
to split sucrose, but it generates fructose and UDP-
glucose instead of glucose. It cannot be excluded that
fructose-specific signalling pathways exist in plants
[64]. Intriguingly, some of the so-called cell wall inver-
tases and sucrose synthases have lost their catalytic
activities, and they may function as regulatory proteins
[65–68], but this requires further investigation. They
are possibly involved in sucrose sensing processes.
Soluble sugars as a part of an
antioxidant system
ROS are continuously produced during mitochondrial
respiration [69,70] and photosynthesis [71]. The mito-
chondrial source of ROS production is as important
in nonphotosynthesizing plant cells as it is in mamma-
lian cells [69]. Small soluble sugars and the enzymes
associated with their metabolic pathways are widely
believed to be connected to oxidative stress and ROS
signalling [10,72–74]. On the one hand, endogenous

sugar availability can feed the oxidative pentose phos-
phate pathway [10,75], creating reducing power for
glutathione (GSH) production, contributing to H
2
O
2
scavenging. On the other hand, excess sugar produc-
tion in source leaves by increased photosynthetic
activities may result in the generation of excess cyto-
solic H
2
O
2
, especially when the export of sugars from
these leaves is hampered due to decreased sink
strength under stress. Therefore, it was proposed that
sugars themselves, especially the longer water-soluble
oligo- and polysaccharides, such as fructans, might be
effective candidates for capturing ROS in tissues
exposed to a wide range of environmental stresses
[17]. Fructans are known to protrude deep between
the headgroups of the membranes (Fig. 2) to stabilize
Stress
H
2
O
2
Cytoplasm
POX
OH

Vacuole
OH +
O +
H
OH
OH +
Fructan
O
Fructan radical
+
H
OH
OH
Fig. 2. A possible dual role for vacuolar fruc-
tans in the vicinity of the tonoplast under
stress. Abiotic and biotic stresses can lead
to increased concentrations of cytosolic
H
2
O
2
, which can enter the vacuole via diffu-
sion and ⁄ or through aquaporins. Vacuolar
fructans (blue) can insert deeply between
the headgroups of the tonoplastic mem-
branes, stabilizing them under stress. Type
III peroxidases (green) associate intimately
with the inner side of the tonoplast. Peroxid-
ases produce
•

OH radicals. Fructans are
well positioned to scavenge these radicals,
a process in which fructan radicals and
water are formed. Fructan radicals might be
generated back into fructans with the help
of phenolic compounds (see also Fig. 1).
M. R. Bolouri-Moghaddam et al. Sugar signalling and antioxidant networks in plants
FEBS Journal 277 (2010) 2022–2037 ª 2010 The Authors Journal compilation ª 2010 FEBS 2025
them [76]. Under stress, excess cytoplasmic H
2
O
2
can
diffuse through the tonoplast (aquaporins can assist
in this process), where tonoplast-bound class III per-
oxidases catalyse the reduction of H
2
O
2
by taking
electrons to various donor molecules, such as phenolic
compounds, lignin precursors, auxin or secondary
metabolites. However, the functioning of these perox-
idases is also accompanied by the production of
•
OH
and
•
OOH through the so-called hydroxylic cycle of
these enzymes [77,78]. Vacuolar fructans are ideally

positioned to stabilize the tonoplast, but also to
temporarily scavenge the aggressive
•
OH and
•
OOH
radicals that are produced in the vicinity of these
membranes (Fig. 2). In this process, the fructans (or
other sugars ⁄ sugar-like compounds) are converted into
(less harmful) fructan radicals. It has been proposed
that such sugar radicals could be recycled back into
sugars with the help of phenolic compounds or antho-
cyanins [17,79]. Interestingly, the synthesis of phenolic
compounds ⁄ anthocyanins can also be stimulated by
sugar-mediated signalling and metabolic pathways
(Fig. 1). Synthetic oligosaccharides also show strong
antioxidant activity in vitro and counteract lipid per-
oxidation processes in mice [80]. In conclusion, it can
be postulated that vacuolar sugars or sugar-like com-
pounds, present in the vicinity of the tonoplast and
interacting with this membrane (Fig. 2), might fulfil
crucial roles in scavenging radicals and thus prevent-
ing lipid peroxidation by excess H
2
O
2
produced under
stress conditions.
Among a range of small sugars tested, sucrose
showed the strongest antioxidant capacity in vitro

[81–83], strongly suggesting that similar antioxidant
reactions with sucrose can also occur in planta. At low
concentrations, sucrose might serve as a substrate or
signal for stress-induced modifications, whereas at
higher concentrations it may function directly as a pro-
tective agent (e.g. in vacuoles of sugar beet and sugar
cane plants, co-operating with the classic, cytoplasmic
antioxidant systems) (Fig. 1) [17].
Other important water-soluble carbohydrates derived
from sucrose (sucrosyl oligosaccharides) include the
raffinose family oligosaccharides (RFOs: a-galactosyl
extensions of sucrose), next to the fructans (b-fructosyl
extensions of sucrose). Sucrosyl oligosaccharides and
the enzymes associated with their metabolism might
interact indirectly with ROS signalling pathways.
Recently, RFOs as well as galactinol have been pro-
posed to fulfil important roles in oxidative stress
protection in plants [81,84] and seeds [85–87]. Previ-
ously, raffinose was shown to protect photophos-
phorylation and electron transport of chloroplast
membranes against freezing, desiccation and high
temperature stress [88], strongly suggesting that chloro-
plastic RFOs might be operating as ROS scavengers.
The oxidized RFO radicals might be regenerated by
ascorbic acid (ASC) or other reducing antioxidants,
such as flavonoids [89]. The overexpression of galacti-
nol synthase (GolS1, GolS2, GolS4) and raffinose syn-
thase in transgenic Arabidopsis plants increased the
galactinol and raffinose concentrations and resulted in
effective ROS scavenging capacity and oxidative stress

tolerance [81]. Moreover, lipid peroxidation was signif-
icantly lower than in wild-type plants. Furthermore,
these transgenic plants exhibited higher photosystem II
(PSII) activities compared with wild-type plants, and
appeared to more tolerant under high light and chilling
conditions [81].
Fructans might protect plants against freezing ⁄
drought stresses by stabilizing membranes [90,91].
Recent studies on transgenic plants carrying fructan
biosynthetic genes [92–94] suggest that the enhanced
tolerance of these plants is associated with the presence
of fructans. Their reduced lipid peroxidation levels
indicate that fructans, similar to RFOs, might also act
directly as ROS scavengers. Alternatively, fructans
might work indirectly by stimulating other specific
antioxidative defence mechanisms [17]. Intriguingly,
changes in fructan concentrations showed a close cor-
relation with changes in ASC and GSH concentrations
in immature wheat kernels, strongly suggesting a con-
nection with the well-known cytoplasmic antioxidant
systems. Therefore, fructans may form an integral part
of a more complex ROS scavenging system in fructan-
accumulating plants. It was proposed that glucose,
produced by the vacuolar fructan initiator enzyme
sucrose : sucrose 1-fructosyl transferase, after retrans-
location to the cytoplasm could directly fuel biosynthe-
sis of classical antioxidants [95,96], establishing a
direct connection between vacuolar and cytoplasmic
antioxidation mechanisms.
Similarly, sugar alcohols (mannitol, inositol, sorbitol)

also possess ROS scavenging capacities. In tobacco,
mannitol is believed to protect thioredoxin, ferredoxin,
GSH and the thiol-regulated enzyme phosphoribulo-
kinase against
•
OH radicals. The targeting of mannitol
biosynthesis to chloroplasts in transgenic tobacco
plants resulted in an increased resistance to methyl
viologen-induced oxidative stress. It became clear that
mannitol in the chloroplast does not reduce ·OH
radical production, but that it increases the capacity to
scavenge these radicals and protects cells against oxida-
tive damages [97]. Contrary to glucose, fructose and
sucrose, mannitol, even at high concentrations, does
not repress photosynthesis and its presence has no
obvious harmful effects on plants [97,98].
Sugar signalling and antioxidant networks in plants M. R. Bolouri-Moghaddam et al.
2026 FEBS Journal 277 (2010) 2022–2037 ª 2010 The Authors Journal compilation ª 2010 FEBS
A role for trehalose in protection against ROS has
also been demonstrated [99]. This is particularly
important in micro-organisms, as only a few plants are
known to accumulate trehalose to a great extent [100].
Trehalose is capable of reducing oxidant-induced mod-
ifications of proteins during exposure of yeast cells to
H
2
O
2
[101]. The ability of trehalose to reduce intracel-
lular oxidation during dehydration has been demon-

strated, especially when yeast cells were deficient in
superoxide dismutase [102]. Moreover, as observed for
fructans, trehalose reduced the levels of lipid peroxida-
tion, suggesting an additional property of this sugar
for improving tolerance to water loss. Also it was
shown that, in vitro, trehalose significantly reduces oxi-
dation of unsaturated fatty acids through a weak inter-
action with the double bonds [103]. The regulated
overexpression of trehalose biosynthetic genes in trans-
genic rice plants produced increased amounts of treha-
lose in the shoot and conferred high levels of tolerance
to salt, drought and low-temperature stresses. Com-
pared with nontransformed rice, several independent
transgenic lines exhibited sustained plant growth, less
photo-oxidative damage and a more favourable
mineral balance under stress conditions [104].
Implication of HXK in sugar signalling
and antioxidant activity
HXKs are ubiquitous proteins in all living beings,
catalysing the phosphorylation of glucose and fructose
[105]. HXKs are not only essential in the first step of
glycolysis. There is also evidence that some HXK
forms are involved in NDP-sugar synthesis [106].
HXKs appear to occur in two groups: one with plastid
signal peptides (type A) and one with N-terminal
membrane anchors (type B) [107], and have been
found in the cytosol, the stroma of plastids, the Golgi
complex [108–113] or associated with the mitochon-
drial membrane [114]. The major glucose phosphory-
lating enzyme in the moss Physcomitrella patens is a

chloroplast stromal HXK [108].
In addition to its familiar role as a metabolic
enzyme, Arabidopsis thaliana HXK1 (AtHXK1) serves
as an intracellular glucose sensor. This sensor is pre-
dominantly associated with mitochondria (mtHXK),
but was also reported to be found in the nucleus
[115,116]. The nuclear AtHXK1 appears to be part of
a glucose signalling complex (Fig. 3) that suppresses
the expression of photosynthetic genes. The signalling
activity of AtHXK1 requires two unexpected partners:
VHA-B1 and RPT5B (Fig. 3). VHA-B1 is one of the
three isoforms of the B subunit of the peripheral V1
complex in vacuolar-type H-ATPase and is responsible
for noncatalytic ATP binding. RPT5B is a subunit of
the 19S regulatory particle, which binds either end of
the 20S proteasome to provide ATP dependence and
the specificity for ubiquitinated proteins. At a low glu-
cose concentration, the target photosynthetic genes are
expressed by a specific transcription factor. At a high
glucose concentration, glucose diffuses into the nucleus
and binds to nuclear HXK1. This process probably
triggers a conformational change in HXK1, which then
acts as a transcriptional repressor together with
VHA-B1 and RPT5B (Fig. 3). In animals, the Mond-
oA ⁄ Mlx complex is believed to monitor intracellular
glucose-6-phosphate concentrations, translocating the
complex to the nucleus when levels of this key metabo-
lite increase. However, nuclear localization of the
MondoA ⁄ Max-like X (Mlx) complex depends on the
enzymatic activity of HXK [117]. In yeast, glucose-

dependent changes in gene expression utilize at least
three mechanisms, including carbon catabolite repres-
sion in which Saccharomyces cerevisiae hexokinase 2
(ScHXK2) has a nonmetabolic role in modulating
specific transcriptional regulators [118]. In maize, the
inhibition of mtHXK by ADP, mannoheptulose and
glucosamine as compared with the insensitive cytosolic
HXK, has been considered as evidence for a putative
role of mtHXK in hexose sensing [109]. However, this
interesting hypothesis awaits more direct demonstra-
tion. Such investigations may also clarify whether (and
under which conditions) HXK is translocated from the
mitochondrion to the nucleus, or mediates distinct
signalling events depending on its subcellular distribu-
tion [119].
The rice OsHXK5 and OsHXK6 proteins appear to
have a similar dual localization and sensor function
[120]. In addition to HXKs, plants also contain several
fructokinases, some of which might also be involved in
sugar sensing [121]. Surprisingly, the AtHXK1 mutant
glucose insensitive 2 is insensitive to glucose, but is still
sensitive to fructose and sucrose [2].
The mitochondrial localization of the HXKs is
thought to improve access to the ATP produced in res-
piration for consumption by active metabolite fluxes
through sucrose cycling, glycolysis and sugar nucleo-
tide synthesis. Consistently, an entire functional glyco-
lytic metabolon appears to be associated with the
outer mitochondrial membrane, allowing pyruvate to
be provided directly to the mitochondrion, where it is

used as a respiratory substrate and glycolytic enzymes
appear to associate dynamically with mitochondria in
response to respiratory demand [122,123].
These observations suggest that mtHXK activity could
be involved in the regulation of both mitochondrial
respiration and ROS production in plants, similar to
M. R. Bolouri-Moghaddam et al. Sugar signalling and antioxidant networks in plants
FEBS Journal 277 (2010) 2022–2037 ª 2010 The Authors Journal compilation ª 2010 FEBS 2027
the key preventive antioxidant role of mtHXK through
a steady-state ADP recycling mechanism in rat brain
neurons [124]. Similar to mammalian HXKs [125,126],
plant mtHXKs have also been reported to associate
with porin ⁄ voltage-dependent anion channels [115],
but further research is needed to unravel the precise
interactions between plant mtHXKs, voltage-depen-
dent anion channels and the outer mitochondrial
membrane. The presence of different hydrophobic
N-terminal sequences in mammalian and plant
mtHXKs suggests that these interactions might sub-
stantially differ between mammals and plants. It was
demonstrated that HXKI and HXKII reduce the intra-
cellular levels of ROS and inhibit the mitochondrial
permeability transition pore in mammalian cells [127].
An authentic mtHXK activity, which is subject to
inhibition by ADP, was detected on potato tuber
(Solanum tuberosum) outer mitochondrial membranes
[128]. A mtHXK activity with similar kinetics has been
described in pea leaves [129]. The potato mtHXK is
much more sensitive to ADP inhibition in the micro-
molar range with glucose as a substrate than with fruc-

tose, suggesting a different affinity for these hexoses
[128]. Moreover, it was demonstrated that this mtHXK
can contribute to a steady-state ADP recycling (ADP
production by mtHXK, bound to the outer mitochon-
drial membrane; ADP consumption through oxidative
phosphorylation) that regulates H
2
O
2
formation in the
electron transport chain on the inner mitochondrial
membrane. Importantly, this mitochondrial ADP recy-
cling mechanism led to a decrease in the mitochondrial
membrane potential, whereas an inhibition of mtHXK
led to an increase in H
2
O
2
production. Thus, mtHXK
bound to the outer mitochondrial membrane can guide
the ADP delivery to the F
0
F
1
ATP synthase enzyme via
the adenine nucleotide transporter in an efficient chan-
nelling to the mitochondrial matrix. In conclusion,
mtHXK activity plays a specific role in generating
ADP to support oxidative phosphorylation, thereby
avoiding an ATP synthesis-related limitation of

Plastid
AB
Mitochondria
26S
proteasome
V-ATPase
Vacuole
Glucose
Nucleus
HXK1
RPT5B
VHA-B1
Fig. 3. The AtHXK1 signalling complex driving the expression of photosynthetic genes in Arabidopsis, depending on the glucose concentra-
tion. (A) When the glucose concentration (white dots) is low, the target photosynthetic genes are turned on by a specific transcription factor
(white). This activation may involve an unidentified coactivator complex. (B) When glucose is in excess (for instance, under nitrate-deficient
conditions or stress condition when invertases are activated, and glucose is not utilized in cells), glucose diffuses freely into the nucleus,
where it binds to nuclear AtHXK1. Glucose binding triggers a conformational change in AtHXK1, which then acts together with VHA-B1
(blue) and RPT5B (yellow) as a transcriptional repressor. Both VHA-B1 and RPT5B interact with the transcription factor, thereby linking
AtHXK1 to DNA binding and suppressing gene expression. The mechanism of the nuclear translocation of AtHXK1, VHA-B1 and RPT5B is
still unknown. This figure has been reproduced from [116] and reprinted with permission from AAAS.
Sugar signalling and antioxidant networks in plants M. R. Bolouri-Moghaddam et al.
2028 FEBS Journal 277 (2010) 2022–2037 ª 2010 The Authors Journal compilation ª 2010 FEBS
respiration and subsequent H
2
O
2
release in plants
[128]. In maize roots, mtHXK activity is believed to be
directly linked to NDP-sugar synthesis (Fig. 1), needed
for cellulose, phenylpropanoid and flavonoid biosyn-

thesis. The attachment of mtHXK to the mitochondrial
membrane is absolutely necessary to perform its preven-
tive antioxidant activity, in both animal and plant mito-
chondria [124,127,128]. Interestingly, both methyl
jasmonate (MeJa) and glucose-6-phosphate are known
to induce the detachment of mammalian mtHXK from
the outer mitochondrial membrane [124,130,131]. Glu-
cose-6-phosphate had no such effect on plant mito-
chondria [128]. The effect of MeJa on the detachment
of mtHXK from plant mitochondria has not yet been
reported. However, MeJa addition to plants leads to
ROS accumulation, alterations in mitochondrial move-
ments and morphology, and cell death [132], similar to
that observed in animal cells [131], suggesting that
similar mechanisms might be operating in plant and
animal cells, but this remains to be demonstrated.
Next to the important signalling function of HXKs,
as described above for AtHXK1, these new data indi-
cate that mtHXK activities might play a key role
as a regulator of ROS levels (Fig. 1). mtHXKs could
respond rapidly to changes in the cellular demand for
glucose-6-phosphate, which is known to be a key inter-
mediate in several metabolic pathways sensitive to
ADP ⁄ ATP ratios, including glycolysis, sucrose synthe-
sis, the pentose phosphate pathway, cellulose biosyn-
thesis and phenylpropanoid and flavonoid biosynthesis
(Fig. 1). However, the links between glucose, HXK
and ROS control extend the processes described in
mitochondria. Indeed, the HXK-derived glucose-6-
phosphate (Fig. 1) can feed the l-galactose route in

the so-called Smirnoff–Wheeler pathway, leading to
biosynthesis of ASC [133], which has major implica-
tions in the well-known cytoplasmic ROS detoxifica-
tion processes, cell elongation and, possibly, cell
division [134]. ASC works in close co-operation with
GSH to remove H
2
O
2
via the Halliwell–Asada path-
way. Moreover, ASC takes part in the regeneration of
a-tocopherol, providing extra protection of the mem-
branes [135]. The NDP-sugars, produced by the activ-
ity of sucrose synthases (and other enzymes), can serve
as donor substrates for glycosyltransferases that cata-
lyse the glycosylation of most plant hormones (except
ethylene), contributing to hormone homeostasis [136].
Moreover, NDP-sugars are also important as donor
substrates for the glycosylation and stability of many
secondary metabolites, such as phenolic compounds
(Fig. 1), contributing to increasing antioxidant abilities
[17] and assisting in recycling sugars from sugar
radicals (Fig. 1). Cellular NDP-sugar concentrations
are often very low. This includes that they are a limit-
ing substrate for product synthesis, as was shown for
(U ⁄ A)DP-glucose-dependent starch biosynthesis in
potato [137] and UDP-glucose-dependent based cellu-
lose synthesis in Avena coleoptiles [138]. Therefore, it
can be postulated that an accumulation of phenolic
compounds would also greatly depend on the cellular

NDP-sugar concentrations, but this requires further
investigation. It is widely recognized that phenolic
compounds are involved in the H
2
O
2
scavenging cas-
cade in plant cells [139], but the links with HXK activ-
ities and sugar recycling processes have so far received
little attention.
Apart from glucose, fructose and sucrose, sugar
alcohols, such as sorbitol, mannitol and myo-inositol,
may also be transported into vacuoles [140,141].
Anthocyanins, flavonoids and a wide array of conju-
gated endogenously synthesized toxic or xenobiotic
compounds typically accumulate in the vacuole and
several of these substances cross the tonoplast via
ATP-binding cassette (ABC)-type carriers [142,143].
Phenolic compounds and fructans (or other vacuolar,
sugar-like compounds) might operate in a synergistic
way to scavenge excess H
2
O
2
(Figs 1 and 2).
Taken together, glucose and HXK take a central
position and a dual role in both sugar signalling and
antioxidant networks, with important links to ASC
biosynthesis and, via NDP- glucose production, to the
synthesis of glycosylated phenolic compounds (Fig. 1).

High concentrations of vacuolar compounds (sugars or
sugar-like compounds) could also form an integral part
of this antioxidant network (Fig. 1).
Senescence – a link between sugar
signalling and ROS production
pathways
In addition to aging, plants are characterized by a
highly specific process termed leaf senescence. After a
period of active photosynthesis, the leaf’s contribution
to the plant diminishes and the leaf then enters its final
stage of development: senescence. This highly regulated
process is characterized by the loss of chlorophyll, the
breakdown of macromolecules and the massive remo-
bilization of nutrients to other parts of the plant [15].
Senescence can be triggered by multiple developmental
and environmental signals. Drought, darkness, leaf
detachment and the hormones ABA and ethylene
induce leaf yellowing [144]. Cytokinins, on the other
hand, can delay plant senescence, and studies with the
AtHXK1 mutant glucose insensitive 2 show that sugars
and cytokinins work antagonistically [19]. Interestingly,
cytokinin-induced cell wall invertase expression is an
M. R. Bolouri-Moghaddam et al. Sugar signalling and antioxidant networks in plants
FEBS Journal 277 (2010) 2022–2037 ª 2010 The Authors Journal compilation ª 2010 FEBS 2029
essential downstream component of cytokinin-medi-
ated local delay (green islands) of leaf senescence [58].
Leaf senescence is accompanied by considerable
changes in cellular metabolism and gene expression
[145]. Several of these senescence-associated genes
encode transporters of sugar, peptides, amino acids

and transporters that could participate in the substrate
and nutrient mobilization that occurs as part of the
senescence programme [146]. However, micro-array
analysis has revealed significant differences in gene
expression between dark ⁄ starvation-induced and devel-
opmental senescence [147].
ROS play an important role in the response of
plants to biotic and abiotic stress, plant cell growth,
regulation of gene expression, stomatal opening, hor-
mone signalling and programmed cell death (PCD)
[148–153]. This multifaceted role for ROS indicates a
tight control of their production and accumulation lev-
els. The observation that ROS may mediate both ABA
signalling and ABA biosynthesis [154] suggests that the
feedback regulation of ABA biosynthetic genes by
ABA may be mediated in part by ROS through a pro-
tein phosphorylation cascade [155]. Senescence-associ-
ated genes are expressed in response to increases in the
tissue contents of ROS [14]. Increased cellular oxida-
tion is a key feature of leaf senescence [14]. PCD may
be triggered by enhanced ROS levels and cellular oxi-
dation [156–158]. Genetic evidence suggests that ROS
do not trigger PCD or senescence by causing physico-
chemical damage to the cell, but rather act as signals
that activate pathways of gene expression that lead to
regulated cell suicide events [152,153]. An imbalance
between ROS production and antioxidant defence can
lead to an oxidative stress condition. Increased levels
of ROS may be a consequence of the action of plant
hormones, environmental stress, pathogens, altered

sugar levels and fatty acids [159–162] and ROS may in
turn induce ROS scavengers and other protective
mechanisms (Fig. 1) [163].
For leaves, evidence supports a role for sugar accu-
mulation in the initiation and ⁄ or acceleration of senes-
cence. However, the regulation of senescence or aging
may respond to different metabolic signals in hetero-
trophic plant organs and heterotrophic organisms
[164]. van Doorn [165] questioned whether sugar
increases or decreases cause leaf senescence, and con-
cluded that there is not enough hard evidence to dem-
onstrate a causative relationship. The long-lasting
debate on this matter probably reflects the complexity
of senescence regulation, with sugars being only one
factor. The initial trigger of processes leading to cell
death probably needs to be searched for in mitochon-
dria [132]. Apart from the actual concentrations of
glucose and sucrose within mitochondria and their sur-
roundings, it becomes increasingly clear that the activ-
ity of mtHXK is essential to regulate ROS levels in
mitochondria (Fig. 1). Although a temporal ROS over-
shoot, via ROS signalling, leads to an increased pro-
duction of antioxidants contributing to ROS
scavenging and stress tolerance, it can be speculated
that a more drastic ROS overshoot could serve as an
initial trigger of senescence. Consistent with this
hypothesis and the central importance of mtHXK
activity, it was recently demonstrated that MeJa addi-
tion, perhaps acting by releasing mtHXK from the
outer membrane, results in four sequential processes:

(a) ROS accumulation, (b) alterations in mitochondrial
movements and morphology, (c) photosynthetic dys-
function and (d) cell death [132].
The Arabidopsis hypersenescing mutant hys1 pro-
vides the clearest link between sugar, senescence and
stress signalling. The repressive effect of sugars on
photosynthetic gene expression and activity and the
correlation between HXK expression and the rate of
leaf senescence [19,21] are indicative of an important
role for HXK-dependent sugar signalling in leaf
senescence. Similar to the effects of targeting the
yeast invertase to chloroplasts, an accelerated senes-
cence was observed during overexpression of HXK
[166]. HXK overexpression in tomato plants
impaired growth and photosynthesis, and induced
rapid senescence in photosynthetic tissues [167]. It
was also demonstrated that mtHXKs play a role in
the control of PCD in Nicotiana benthamiana [168].
HXK dislocation from mitochondria leads to the
closure of voltage-dependent anion channels and sub-
sequent mitochondrial swelling and cell death in
mammalian cells [169]. HXK binding to the mito-
chondria inhibits apoptosis [169]. Increasing glucose
phosphorylation activity by mtHXK may reduce
apoptosis through both the inhibition of mitochon-
drial permeability transition and more efficient
glucose metabolism due to their better access to
ATP [127].
In conclusion, plant mtHXKs might act as a glucose
sensor (regulatory function) and, through its catalytic

activity, as a crucial regulator of ROS levels in mito-
chondria (Fig. 1). Similar functions could be postu-
lated for chloroplastic HXKs.
All abiotic stresses generate ROS, potentially leading
to oxidative damage affecting crop yield and quality.
Next to the well-known classical antioxidant mecha-
nisms, sugars and sugar metabolizing enzymes come
into the picture as important new players in the
defence against oxidative stress. Therefore, sugar
metabolizing enzymes, such as organellar HXKs, form
Sugar signalling and antioxidant networks in plants M. R. Bolouri-Moghaddam et al.
2030 FEBS Journal 277 (2010) 2022–2037 ª 2010 The Authors Journal compilation ª 2010 FEBS
promising targets to improve crop yield, stress toler-
ance and longevity in plants.
Conclusion
Sugars are finally being recognized as important regu-
latory molecules with both signalling and putative
ROS scavenging functions in plants [2] and other
organisms [170–172]. The exact source, nature and
location of the sugar and nonsugar signals, such as
ROS and hormones, are important to provide an inte-
grative regulatory mechanism controlling various func-
tions of a plant cell. The responses to sugars and
oxidative stress are not only linked (Fig. 1), but sugars
also affect scores of stress-responsive genes [27]. Apart
from acting as signals, we hypothesize that vacuolar
sugars or sugar-like compounds, possibly in combina-
tion with phenolic compounds, form a so far unrecog-
nized vacuolar redox system acting in concert with the
well-established cytoplastic antioxidant mechanisms.

Acknowledgements
WVdE, KLR, LX and FR are supported by grants
from FWO Vlaanderen.
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