Biol. Chem., Vol. 393, pp. 999–1004, September 2012 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.
1515/hsz-2012-0111
Minireview
Redox Biology on the rise
Johannes M. Herrmann1 and Tobias P. Dick2,*
1
Zellbiologie, Technische Universität Kaiserslautern, Erwin-
Schrödinger-Str. 13, D-67663 Kaiserslautern, Germany
2
Division of Redox Regulation, DKFZ-ZMBH Alliance,
German Cancer Research Center (DKFZ), Im Neuenheimer
Feld 280, D-69120 Heidelberg, Germany
* Corresponding author
e-mail: t.dick@dkfz.de
Abstract
Redox reactions are at the heart of bioenergetics, yet their bio-
logical role is not restricted to metabolism. One specific focus
of contemporary Redox Biology is the study of how the fold-
ing, stability, activity, and interactivity of proteins are subject
to redox control. Key questions pertain to the chemical nature
of physiological redox changes and their exact location inside
the cell, the nature and distribution of protein redox modifi-
cations, and their meaning for cellular physiology. In recent
years, Redox Biology has developed novel methodological
directions, for example, the proteomic profiling of protein
redox modifications and the noninvasive monitoring of redox
processes in vivo. These and other approaches allow asking
new questions for which the answers are almost completely
unknown. To stimulate exchange of technical knowledge and
the appreciation of Redox Biology in general, the German
Society for Biochemistry and Molecular Biology (GBM)
recently founded a Study Group for Redox Biology.
Keywords: Redox Biology; redox regulation; thiol oxidation.
‘Redox Biology ’ is at the heart of Life Sciences
Looking at life from the perspective of electron flow may
be one of the most universal and fundamental approaches
to Biology. This is because all known life forms depend on
electrons that get stranded at the top of ‘energy hills,’ wait-
ing to roll down the hill toward a low-energy resting place.
This insight has been famously expressed in the words of
Albert Szent-Györgyi: ‘Life is nothing but electrons looking
for a place to rest’ (Trefil et al., 2009). Primordial organisms,
like the chemolithoautotrophic bacteria, harvest geochemical
gradients of electronic energy. Other autotrophic organisms
actively create new redox gradients for consumption, most
prominently by employing sunlight to push resting elec-
trons to the top of energy hills. Yet other organisms, like us
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heterotrophic aerobes, depend on the environmental redox
gradients created by autotrophs. Thanks to the restrictive
rules of quantum mechanics, most high-energy electrons do
not fall back to low-energy states spontaneously. They need
to be offered feasible pathways. It is the facilitated and tightly
controlled rearrangement of electrons along the energy scale
that makes life possible. A number of electrons move toward a
new resting place, the terminal acceptor, which for us aerobes
is molecular oxygen, yielding water. Not all electrons take the
most direct route to low-energy states; many take convoluted
detours to dissipate their energy in special ways. Electrons
on their way from the fuel molecules to the terminal accep-
tor drive both oxidative and reductive processes. Incomplete
reduction of molecular oxygen leads to oxygen species that
seek complete reduction and therefore play roles as oxidants.
It may seem that the scope of Redox Biology is mostly
restricted to metabolism per se, but a much wider scope has
become apparent over the years, namely, the growing real-
ization that the re-distribution of electrons across energy
levels not only drives chemical disequilibria and bond rear-
rangements but also instructs cellular organization at all lev-
els of regulation. Cells sense changes in electronic energy
distribution in real time and take account of their electronic
status when making cell fate decisions, from differentiation
to cell death. How does electron flux inform the rest of the
cell? The plant physiologists were among the first to recog-
nize specific molecular interfaces between electron flux and a
broad range of cellular functions, namely, the dynamic mak-
ing and breaking of regulatory protein disulfide bridges that
adapt enzyme activities in the chloroplast stroma to light-
driven electron flux (Buchanan and Balmer, 2005). Indeed,
the need to continuously adapt the whole physiology of an
organism to electron flux is nowhere else more obvious than
in the plant kingdom, where both uphill and downhill electron
movements have to be coordinated within the same cells, and
the real-time dynamic response to a changing environment
is more critical for survival than in those organisms that can
actively move around to seek out better environmental condi-
tions. Nevertheless, it is now clear that redox regulation of
protein function is not restricted to plants, but is found every-
where in Biology.
In the broadest sense, Redox Biology aims at understand-
ing the coupling and coordination between electron gradients
and the overall organization of living organisms. In between,
at the interface between electron flow and cellular func-
tions, are the redox modifications of cellular components. As
such, Redox Biology is an extremely broad field that covers
metabolism, free radical and oxidative stress biology (Chance
et al., 1979; Sies, 1986), sulfur and selenium chemistry (Jacob
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1000 J.M. Herrmann and T.P. Dick
et al., 2003; Winterbourn and Hampton, 2008), and many
other aspects. Considering the central role of proteins as cata-
lysts and targets of redox processes, we here focus on a spe-
cific sector of Redox Biology, namely, the study of how the
folding, stability, activity, and interactivity of proteins is sub-
ject to redox control. In recent years, this area has developed
key concepts and novel methodological directions.
Some of the key concepts are depicted in Figure 1: on
the one hand, in some cellular compartments like the bac-
terial periplasm, the endoplasmic reticulum (ER), and the
intermembrane space (IMS) of the mitochondria, dedicated
enzyme systems introduce and reshuffle disulfide bonds. In
these compartments, oxidative folding is the general principle
to stabilize protein structure (Figure 1A) (Sevier and Kaiser,
2002; Tu and Weissman, 2004; Riemer et al., 2009). On the
other hand, in the cytosol, the nucleus and the mitochondrial
matrix, protein folding is non-oxidative per se; nevertheless,
protein thiols are often oxidized, and various oxidative post-
translational modifications modulate protein function in these
Figure 1 Pathways of protein thiol oxidation.
(A) The oxidative folding of proteins is a general principle to sta-
bilize protein structures in the periplasm of bacteria, the mitochon-
drial IMS, and the secretory pathway including the ER. In these
compartments, electrons from cysteine residues are transferred via
oxidoreductases and thiol oxidases to molecular oxygen which, at
least under aerobic conditions, serves as final electron acceptor. (B)
In the cytosol, the nucleus, and the mitochondrial matrix, protein
thiols are largely reduced. Still, individual cysteine residues can be
modified by a number of chemically different oxidation reactions
thereby influencing the activity or stability of proteins. (C) A num-
ber of dedicated reducing enzymes reverses these oxidation reactions
and brings proteins back into their reduced state. Hence, the levels
of reduced and oxidized states of thiols in the cytosol, the nucleus,
and the mitochondrial matrix are influenced – with or without the
assistance of enzymes – by the levels of small oxidizing or reducing
compounds like hydrogen peroxide or GSH, respectively.
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compartments (Figure 1B) (Paget and Buttner, 2003; Barford,
2004; Ghezzi, 2005; Reddie and Carroll, 2008; Brandes
et al., 2009; Hansen et al., 2009). How proteins are specifi-
cally and efficiently oxidized for regulatory purposes is not
yet fully understood. Some thiol oxidations may be the result
of direct encounters with small-molecule oxidants, but oth-
ers depend on specific facilitation by redox catalysts. In any
case, the reversal of oxidative modifications depends on a set
of coupled redox catalysts, most prominently the thioredoxin
and glutathione systems (Figure 1C) (Holmgren et al., 2005;
Lillig and Holmgren, 2007). In the following paragraph, we
briefly summarize how the concepts of protein thiol oxidation
have evolved during the last 10 years.
Shifting viewpoints in protein thiol oxidation
Until a few years ago, disulfide bond formation in proteins
was regarded as a simple matter. Cellular compartments con-
tain a thiol-disulfide redox pair at millimolar concentration,
the glutathione (GSH)-glutathione disulfide (GSSG) couple,
which was considered to be in equilibrium with protein thiols.
Accordingly, it was thought that the glutathione-based ‘redox
buffer ’ or ‘redox environment’ of a given compartment deter-
mined the redox state of protein thiols. It followed that the
cytosol had to be a strictly reducing environment that does
not allow formation of protein disulfide bonds. Likewise, the
thiol-oxidizing power of the ER environment was explained
by its relatively high GSSG to GSH ratio (Hwang et al.,
1992). It was assumed that protein thiols engage in disulfide
exchange with GSSG spontaneously, thus forming inter- and
intramolecular disulfide bonds.
Since then, our picture of disulfide bond formation
in vivo has changed substantially: for all intents and purposes,
to be relevant on biological time scales, in vivo thiol oxida-
tion by molecular oxygen always appears to be a catalyzed
and organized process, mediated by cascades of specialized
redox enzymes, most prominently oxidoreductases and thiol
oxidases. In particular, the path of electrons from protein
thiols to molecular oxygen has been tracked carefully in the
periplasmic space, the ER and the IMS, in each case revealing
specific redox relays based on protein-protein contacts, the
coupling between oxidoreductases and thiol oxidases being
central in each case (Riemer et al., 2009). Almost ironically,
it now seems clear that the relatively high GSSG/GSH ratio
in the ER is much less a cause of protein disulfide forma-
tion than is its consequence: to a large part, the high levels of
GSSG appear to result from reduction of inappropriate pro-
tein disulfides as part of a quality control mechanism (Cuozzo
and Kaiser, 1999).
The purpose of making disulfides in secretory proteins is
the increased structural stabilization that disulfide bonds pro-
vide. Owing to the activity of the oxidation machineries, most
protein thiols in the secretory pathway and periplasm are oxi-
dized. Nevertheless, recently published studies indicate that
by catalyzed reductions and rearrangements of disulfides,
proteins can be regulated within the secretory pathway and
on the cell surface, e.g., during viral entry (Ryser et al., 1994;
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Schelhaas et al., 2007). Catalyzed reduction also modulates
the activity of the oxidation machinery in the ER. Thus, even
in a generally oxidizing compartment, protein activity can be
controlled by redox regulation.
The emergent role of protein thiols and disulfides as func-
tional switches also characterizes the change of viewpoint that
has taken place for the cytosol. More and more, it is realized
that disulfides and other forms of thiol oxidation regulate pro-
tein functions posttranslationally. The regulation of protein
function by transient oxidative thiol modifications may be as
common and important as protein phosphorylation. Recent
studies suggest that during exponential growth, a significant
fraction of protein thiols in the yeast cytosol is always oxidized
to some degree (Hansen et al., 2009; Brandes et al., 2011). In
the cytosol, the predominant proximate thiol oxidant is H2O2,
not molecular oxygen. H2O2 is frequently assumed to react
readily with thiols, but many protein thiols that become oxi-
dized in the cell do not seem to be sufficiently reactive toward
H2O2 (Winterbourn, 2008). Kinetic measurements reveal that
even low-pKa cysteines react with H2O2 relatively slowly
(∼101–102 m-1 s-1), several orders of magnitude slower than
the thiols of ‘professional’ H2O2 scavengers (∼105–107 m-1 s-1),
the peroxiredoxins and glutathione peroxidases (Winterbourn
and Hampton, 2008). It turns out that some thiol peroxidases
are actually able to pass on oxidative equivalents to particu-
lar proteins during specific protein-protein contacts. The best
known example is the yeast ‘signaling peroxidase’ Orp1,
which oxidizes the transcription factor Yap1 (Delaunay et al.,
2002). Several other peroxidase-transcription factor redox
relays have been identified in yeast where there is now strong
evidence for genome-wide regulation of gene expression by
thiol peroxidases (Fomenko et al., 2011). Perhaps such per-
oxidase redox relays also exist in mammalian cells. Thus,
thiol peroxidases seem to join an emerging theme, namely,
that enzymes we traditionally consider as ‘antioxidant’ are not
just passive disposers of oxidants but active participants in
redox signaling. Overall, thiol oxidation and reduction, nowa-
days, looks more like a controlled process, and it seems that
this trend continues (Finkel, 2011). It is now quite clear that
H2O2 is the reactive oxygen species most relevant to cell sig-
naling. Not only is oxidant generation by NADPH oxidases
Figure 2 Central questions in Redox Biology.
See text for details.
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Redox Biology on the rise 1001
a tightly regulated process but also oxidant diffusion and life
time are much more controlled than previously thought pos-
sible. For example, recent evidence suggests that movement
of H2O2 across membranes requires specific channels (Miller
et al., 2010) and that its diffusion away from the site of origin
is sharply controlled by the local activity of thiol peroxidases,
which are themselves dynamically regulated by phosphoryla-
tion (Woo et al., 2010).
New and improved tools for Redox Biology
Whatever the redox-related phenomenon under study is, there
is a set of critical questions that Redox Biology has to answer
(Figure 2). These questions are not novel, but there are new
ways to approach them (Figure 3). First of all, whenever a
redox state or a redox change is to be measured or observed,
there is the question of the specific chemistry behind it.
The common use of umbrella terms (‘reactive oxygen spe-
cies’) and broad concepts (‘oxidative stress’) is not helpful
to describe the actual chemistry, yet the use of such terms
can have value and utility as long as their limitations are kept
in mind. Nevertheless, whenever possible, the use of non-ex-
plicit terms should be avoided as it is likely to create confu-
sion and lead to untestable hypotheses. As much as possible,
the goal of Redox Biology must be to make statements with
chemical precision (Murphy et al., 2011). The specific quan-
titation and visualization of defined oxidants and small mol-
ecule redox couples has always been challenging and prone to
artifacts. Yet, two remarkable developments have taken place
over the last couple of years: on the one hand, small molecule
probes have been made more sensitive and specific (Chen et
al., 2011), one example being the boronate caging of fluoro-
phores, which affords H2O2 specificity (Miller et al., 2007).
On the other hand, genetically encoded redox probes have
been developed, and some of them have been made respon-
sive toward defined oxidants or redox couples (Meyer and
Dick, 2010). One important example is HyPer, a probe for
H2O2 based on circularly permuted yellow fluorescent protein
(cpYFP) (Belousov et al., 2006). Other prominent examples
are the reduction-oxidation-sensitive GFPs (roGFPs) (Dooley
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1002 J.M. Herrmann and T.P. Dick
Figure 3 Methodological advances.
Many novel tools and methods were developed only recently. This Figure highlights a few of these that are instrumental for the detection or
quantification of small oxidizing molecules as well as of oxidative modifications of proteins.
et al., 2004) and their derivatives, which are now used to mea-
sure the glutathione redox potential (Gutscher et al., 2008)
and to observe relative differences and changes in H2O2 levels
(Gutscher et al., 2009). Of note, the most recent development
are genetically encoded probes for the NAD+/NADH redox
couple (Hung et al., 2011b).
Second, there is the question of location. Where exactly does
a redox change take place: in which cells of an organism, and
in which subcellular compartment or microenvironment inside
the cell? As the regulation of redox processes is largely com-
partment specific, measurements of redox states must also be
compartment specific. Although frequently encountered in the
literature, statements about the overall ‘cellular redox state’
are not appropriate, as they usually fail to acknowledge the
chemical and spatial differentiation of intracellular redox pro-
cesses. Again, it is the genetically encoded redox probes that
offer opportunities to uncover the spatial distribution of redox
processes. These probes can be expressed in defined subcel-
lular compartments or even be targeted to specific locations
within one compartment (Mishina et al., 2011). On the organis-
mal level, genetically encoded probes are now paving the way
toward in vivo mapping of redox species across whole multi-
cellular organisms (Albrecht et al., 2011; Back et al., 2012).
Despite these promising developments, it must not be forgot-
ten that even the most current probes have their limitations and
potential pitfalls that must be kept in mind when designing con-
trols and drawing conclusions (Meyer and Dick, 2010).
Third, whenever a redox change takes place, there is the
question of how it influences the behavior of target proteins.
Which proteins are redox regulated and responsive to an oxi-
dant in a particular physiological situation? Which residues
within those proteins are affected? What kind of oxidative
modifications take place on these residues? Which addi-
tional factors determine or mediate the formation and reso-
lution of reversible oxidative modifications? Over the last
years, the field of ‘redox proteomics’ has been emerging and
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increasingly allows global analysis of protein redox states.
Of particular mention is the oxICAT (isotope coded affinity
tag for oxidative thiol modifications) technique, which spe-
cifically maps reversible protein thiol modifications (Leichert
et al., 2008). The chemical tool kit that allows researchers to
trap and label thiols of individual proteins, in particular redox
states, has also been expanded and improved (Leonard and
Carroll, 2010). In particular, the increasing ability to monitor
the oxidation of cysteines to sulfenic acid residues (Leonard
et al., 2009) has led to new insights (Depuydt et al., 2009).
Despite these developments, it can be said that our knowledge
of protein redox modifications and of protein redox regulation
remains ‘insular.’ Some enzymes, e.g., protein tyrosine phos-
phatases, have received particular attention (Karisch et al.,
2011), but the overall landscape of protein redox regulation
remains largely uncharted. It seems that the number of redox-
regulated proteins and also the number of redox-regulated
sites within one protein is higher than originally suspected.
The scope of protein redox modifications may be similar to
that of phosphorylation or ubiquitinylation. Interestingly, it
now appears that protein function can also be regulated by
reversible oxidation of methionine residues (Hung et al.,
2011a).
Fourth, there is another key question for which Redox
Biology has to provide an answer: how are we going to inves-
tigate causality and biological relevance of redox processes?
Why do certain redox changes occur at all? What is their bio-
logical meaning and significance? What exactly is caused by
these changes? To find answers to such questions, we need to
be able to manipulate individual redox processes in a specific
manner; for example, one has to lower or increase the genera-
tion of defined oxidants in defined places, or change the thiol
redox state of a defined protein, with minimal impact on other
processes. It is probably fair to say that most pharmacological
strategies commonly used to manipulate endogenous redox pro-
cesses (and to make claims about biological roles of oxidants)
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do not offer the specificity that would be needed for drawing
solid conclusions (Murphy et al., 2011). Specific manipulations
are easier to accomplish by genetic tools and on the protein
level. For example, it is often desired to convert a redox-sensi-
tive protein into a redox-insensitive variant (i.e., by mutating a
particular cysteine residue), but without altering its expression
level or genomic regulation. The emerging tools of genome
editing in mammalian cell lines, based on sequence-specific
endonucleases (McMahon et al., 2011), will be increasingly
used to routinely introduce targeted point mutations into the
genomic locations encoding redox-regulated proteins.
In conclusion, various emerging techniques progressively
open a window into the world of biological redox processes.
Unexpected observations are being made, and many new
questions can be asked, for which the answers are almost
completely unknown. For example, do redox and non-redox
posttranslational modifications frequently talk to each other
in signal transduction, perhaps thiol oxidation being a pre-
requisite for nearby phosphorylation, or vice versa?
The biomedical frontier of Redox Biology
What may be the future contribution of Redox Biology to
the understanding of human disease? It is increasingly clear
that some traditional concepts about the role of oxidants in
Biology do not provide a sustainable framework for future
research. The significance of ‘reactive oxygen species’ (ROS)
as damaging agents and drivers of disease and aging remains
highly controversial (Murphy et al., 2011). On the contrary,
the action of certain oxidants, in particular H2O2, is now well
recognized as a positive and essential part of healthy physi-
ology. In study after study, conventional ‘antioxidants’ have
failed to fulfill their promise (e.g., Goodman et al., 2011).
Nonetheless, there is little doubt that endogenous oxidants
and protein redox regulation are central to health and disease,
but most likely in ways quite different from what has been
originally envisaged. For example, there seem to be very close
regulatory interrelationships between mitochondrial oxidant
generation, mitogenesis, mitophagy, and mitochondrial-nu-
clear communications (Green et al., 2011; Kanki et al., 2011;
Youle and Narendra, 2011). Oxidants are deeply involved in
regulatory loops central to immunity, inflammation, and the
cell death decision (West et al., 2011). Rather than the accu-
mulation of ‘oxidative damage,’ it may be changes in these
regulatory networks that are relevant to disease and aging.
The GBM study group Redox Biology
The analysis of redox processes is often technically difficult.
Although many of the newly developed techniques rely on
relatively simple concepts and seem to be straightforward
experimentally, they often lead to artifacts due to problems
in how the experiments are carried out and how the results
are interpreted. For the use of protein-modifying reagents and
GFP-based redox sensors, a basic understanding of their chem-
istry and some experience with the interpretation of the data
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Redox Biology on the rise 1003
is important. Cell lysis easily causes artificial thiol oxidation,
and thiol-modifying reagents may not reach all thiols equally;
both complications can lead to the overestimation of protein
oxidation. The identification by mass spectrometry of cysteine
modifications and of disulfide connectivity in a given protein
can be difficult and needs expertise. To stimulate exchange
of technical knowledge, and also to foster the appreciation
of Redox Biology, the German Society for Biochemistry and
Molecular Biology (GBM) recently founded a new Study
Group for Redox Biology. This group will organize annual
meetings as well as web-based interaction platforms for its
members. For more information, please contact the authors
or see the GBM homepage (www.gbm-online.de). The full
picture and complexity of Redox Biology is ready to unfold,
and we hope that this Study Group can contribute to shedding
light on this exciting aspect of Biology.
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Received January 27, 2012; accepted May 11, 2012
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