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“Oxidative stress” as a concept in redox biology and medicine has been formulated in 1985; at the beginning of 2015, approx. 140,000 PubMed entries show for this term. This concept has its merits and its pitfalls. Among the merits is the notion, elicited by the combined two terms of (i) aerobic metabolism as a steady-state redox balance, and (ii) the associated potential strains in the balance as denoted by the term, stress, evoking biological stress responses. Current research on molecular redox switches governing oxidative stress responses is in full bloom. The fundamental importance of linking redox shifts to phosphorylation/dephosphorylation signaling is being more fully appreciated, thanks to major advances in methodology. Among the pitfalls is the fact that the underlying molecular details are to be worked out in each particular case, which is bvious for a global concept, but which is sometimes overlooked. This can lead to indiscriminate use of the term, oxidative stress, without clear relation to redox chemistry. The major role in antioxidant defense is fulfilled by antioxidant enzymes, not by small-molecule antioxidant compounds. The field of oxidative stress research embraces chemistry, biochemistry, cell biology, physiology and pathophysiology, all the way to medicine and health and disease research.
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Oxidative stress: a concept in redox biology and
Helmut Sies
PII: S2213-2317(15)00003-8
Reference: REDOX247
To appear in: Redox Biology
Received date: 28 December 2014
Accepted date: 1 January 2015
Cite this article as: Helmut Sies, Oxidative stress: a concept in redox biology and
medicine, Redox Biology,
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Oxidative stress: a concept in redox biology and medicine
Helmut Sies
Institute of Biochemistry and Molecular Biology I, Heinrich-Heine-University Düsseldorf,
Düsseldorf, Germany
For correspondence:Helmut Sies, Institute of Biochemistry and Molecular Biology I,
Heinrich-Heine-University Düsseldorf, Building 22.03, University Street 1, D-40225-
Düsseldorf, Germany., Phone: +49-211-8115956
“Oxidative stressas a concept in redox biology and medicine has been formulated in 1985;
at the beginning of 2015, approx. 140,000 PubMed entries show for this term. This concept
has its merits and its pitfalls. Among the merits is the notion, elicited by the combined two
terms of (i) aerobic metabolism as a steady-state redox balance, and (ii) the associated
potential strains in the balance as denoted by the term, stress, evoking biological stress
responses. Current research on molecular redox switches governing oxidative stress
responses is in full bloom. The fundamental importance of linking redox shifts to
phosphorylation/dephosphorylation signaling is being more fully appreciated, thanks to major
advances in methodology. Among the pitfalls is the fact that the underlying molecular details
are to be worked out in each particular case, which is obvious for a global concept, but which
is sometimes overlooked. This can lead to indiscriminate use of the term, oxidative stress,
without clear relation to redox chemistry. The major role in antioxidant defense is fulfilled by
antioxidant enzymes, not by small-molecule antioxidant compounds. The field of oxidative
stress research embraces chemistry, biochemistry, cell biology, physiology and
pathophysiology, all the way to medicine and health and disease research.
Oxidative stress, redox balance, oxidants, antioxidants, redox signaling, adaptive response
Oxidative stress denotes deviation from redox steady state
Oxidative stress is an attribute of aerobic metabolism
Oxidative stress evokes stress responses
Oxidative stress activates molecular redox switches
The concept of oxidative stress has been introduced for research in redox biology
and medicine in 1985, now 30 years ago, in an introductory chapter (1) in a book entitled
'Oxidative Stress' (2). A concurrent comprehensive review entitled 'Biochemistry of
Oxidative Stress' (3) presented the knowledge on pro-oxidants and antioxidants and their
endogenous and exogenous sources and metabolic sinks. Since then, Redox Biology as a
research area has found fulminant development in a wide range of disciplines, starting from
chemistry and radiation biology through biochemistry and cell physiology all the way into
general biology and medicine.
A noteworthy insight, early on, was the perception that oxidation-reduction (redox)
reactions in living cells are utilized in fundamental processes of redox regulation, collectively
termed 'redox signaling' and 'redox control'. A book 'Antioxidant and Redox Regulation of
Genes' highlighted that development at an early stage (4). Since then, an overwhelming and
fascinating area of research has flourished, under the name of Redox Biology (5,6). The
concept of oxidative stress was updated to include the role of redox signaling (7), and there
were efforts of redefining oxidative stress (8, 9).
These developments were mirrored by the appearance of monographs, book series
and the establishment of new research journals. Many volumes were published in Methods in
Enzymology. An impressive number of new journals sprang up, Free Radical Research
(initially Free Radical Research Communications), Free Radicals in Biology and Medicine,
Redox Reports, Antioxidant Redox Signaling, and most recently Redox Biology.
Useful as the term 'oxidative stress' may be in research, there has been an
inflationary development in research circles and more so in the medical field and, even more
than that, in public usage outside scientific endeavors (I would call it ‗over-stressing‘ the
term). This led to a dilution of the meaning, to overuse and even misuse. Cautionary words
were published (10) and even explicit criticism was voiced (11,12). ―Over time, the
mechanistic basis of the concept was largely forgotten and instead of the oxidative stress
hypothesis becoming more precise in terms of molecular targets and mechanism, it became
diffuse and nonspecific‖ (12). In fact, an ‗oxidative stress hypothesis‘ has not been
formulated up to now. If anything, there were implicit deductions: for example, that because
of the redox balance concept any single compound, e.g. a small-molecule redox-active
vitamin, could alter the totality of the system. Such a view overlooks counterregulation and
redundancies in the redox network. There is specificity inherent in the strategies of
antioxidant defense (13). Obviously, a general term describing a global condition cannot be
meant to depict specific spatiotemporal chemical relationships in detail and in specific cells or
organ conditions. Rather, it entails these, and directed effort is warranted to unravel the exact
chemical and physical conditions and their significance in each case.
Given the enormous variety and range of pro-oxidant and antioxidant enzymes and
compounds, attempts were made to classify subforms of oxidative stress (7) and to
conceptually introduce intensity scales ranging from physiological oxidative stress to
excessive and toxic oxidative burden (14), as indicated in Table 1.
What are the merits and pitfalls of 'oxidative stress' today?
A comprehensive treatment of this question is to be deferred to an in-depth
treatment (in preparation). However, for the purpose of the present Commentary it may
suffice to collect a few thoughts: from its very nature, it is a challenge to combine the basic
chemical notion of oxidation-reduction, including electron transfer, free radicals, oxygen
metabolites (such as the superoxide anion radical, hydrogen peroxide, hydroxyl radical,
electronically excited states such as singlet molecular oxygen, as well as the nitric oxide
radical and peroxynitrite) with a biological concept, that of stress, first introduced by Selye in
his research of adaptive responses (15,16). The two words 'oxidative' and 'stress' elicit a
notion which, in a nutshell, focuses on an important sector of fundamental processes in
biology. This is a merit.
Pitfalls are close-by: in research, simply to talk of exposing cells or organisms to
oxidative stress should clearly be discouraged. Instead, the exact molecular condition
employed to change the redox balance of a given system is what is important; for example, in
an experimental study cells were exposed to hydrogen peroxide, not to oxidative stress. Such
considerations are even more appropriate in applications in the medical world. Quite often,
redox components which are thought to be centrally important in disease processes are flatly
denoted as oxidative stress; this can still be found in numerous schemes in the current
biomedical literature. The underlying biochemically rigorous foundation may often be
missing. Constructive criticism in this sense has been voiced repeatedly (11,12,17). A related
pitfall in this sense is the use of the term ROS, which stands for reactive oxygen species (the
individual chemical reactants which were named in the preceding paragraph); whenever the
specific chemical entity of the oxidant is known, that oxidant should be mentioned and
discussed, not the generic ‗ROS‘.
This ‗one-size-fits-all‘ mentality pervades also into the analytics: measuring so-
called ‗total antioxidant capacity (TAC)‘ in a blood plasma sample will not give useful
information on the state of the organism, and should be discouraged (18). Rather, individual
antioxidant enzyme activities and patterns of antioxidant molecules need to be assessed.
In view of the knowledge that the major burden of antioxidant defense is shouldered
by antioxidant enzymes (13), it seems puzzlingin hindsightthat large human clinical
studies based on one or two low-molecular-weight antioxidant compounds were undertaken.
What is attractive about ‘oxidative stress’?
Molecular redox switches. What seems to be attractive about the term is the implicit
notion of adaptation, coming from the general association of stress with stress response. This
goes back to Selye‘s concept of stress as the ‗general adaptation syndrome‘ (19). The
enormously productive field of molecular switches was opened by the discovery of
phosphorylation/dephosphorylation, serving a mechanism in molecular signaling (20). The
role of redox switches came into focus more recently, foremost the dynamic role of cysteines
in proteins, opening the field of the redox proteome, currently flourishing because of advances
in mass spectrometric and imaging methodology (21-24). A bridge between
phosphorylation/dephosphorylation and protein cysteine reduction/oxidation is given by the
redox sensitivity of critical cysteinyl residues in protein phosphatases, opening the molecular
pathway for signaling cascades as fundamental processes throughout biology,
What was particularly exciting to many researchers was the discovery of master
switch systems (25), prominent examples being OxyR in bacteria (26) and NFkB (27) and
Nrf2/Keap1 (28 ) in higher organisms. That batteries of enzyme activities are mustered by
activation of gene transcription through a 'simple' redox signal is still an exciting strategy.
Much of current effort in redox biology is addressed towards these response systems.
Obviously, medical and pharmacological intervention attempts are a consequence.
Current interest into the linkage of oxidative stress to inflammation and inflammatory
responses is adding a new perspective. For example, inflammatory macrophages release
glutathionylated peroxiredoxin-2, which then acts as a ‗danger signal‘ to trigger the
production of tumor necrosis factor-alpha (29). The orchestrated responses to danger signals
related to damage-associated molecular patterns (DAMPs) include relations to oxidative stress
(30). Under oxidative stress conditions, a protein targeting factor, Get3 in yeast (mammalian
TRC40) functions as an ATP-independent chaperone (31). More detailed molecular
understanding will also deepen the translational impact into biology and medicine; as
mentioned above, these aspects are beyond this Commentary and will be treated elsewhere.
However, it might be mentioned, for example, that viral and bacterial infections are often
associated with deficiencies in micronutrients, including the essential trace element, selenium,
the redox-active moiety in selenoproteins. Selenium status may affect the function of cells in
both adaptive and innate immunity (32). Major diseases, now even diabetes Type 2, are being
considered as ‗redox disease‘ (33).
Molecular insight will enhance the thrust of the concept of oxidative stress, which is
intimately linked to cellular energy balance. Thus, the subcellular compartmentation of redox
processes and redox components is being studied at a new level, in mammalian cells (34) as
well as in phototrophic organisms (35). New insight from spatiotemporal organisation of
hydrogen peroxide metabolism (36) complements the longstanding interest in hydroperoxide
metabolism in mammalian organs and its relationship to bioenergetics (37).
The following quote attributed to Hans Selye [38] might well apply to the concept of
oxidative stress: ― If only stress could be seen, isolated and measured, I am sure we could
enormously lengthen the average human life span‖.
I gratefully acknowledge the input and friendship of many colleagues in shaping ideas in this
multidisciplinary field; of many close associates, Enrique Cadenas and Wilhelm Stahl in
particular, and close colleagues Dean Jones, Bruce Ames, Lester Packer, Alberto Boveris.
Also to Masayasu Inoue for the translation of the book ‗Oxidative Stress‘ into Japanese. Last,
but not least, to the many active scientists in this research field, gathered under the umbrella
of the Society for Free Radical Research International (SFRRI) and related organisations such
as the Oxygen Club of California (OCC).
I also am thankful for the research support by the National Foundation of Cancer
Research (NFCR), Bethesda, MD, USA, and the Deutsche Forschungsgemeinschaft and the
Alexander-von-Humboldt Foundation.
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Graphical Abstract
Table 1.
Oxidative Stress: definition, specific forms, classification according to intensity.
Category Term Reference
Definition, original ―A disturbance in the prooxidant-antioxidant [1]
balance in favor of the former‖
updated ―An imbalance between oxidants and antioxidants [7]
in favor of the oxidants, leading to a disruption
of redox signaling and control and/or molecular
Specific form Nutritional oxidative stress [7]
Dietary oxidative stress
Postprandial oxidative stress
Physiological oxidative stress
Photooxidative stress
Ultraviolet (UV-A, UV-B)
Radiation-induced oxidative stress
Nitrosative stress
Reductive stress
Related terms Oxidant stress, Pro-oxidant stress
Oxidative stress status (OSS)
Classification Basal oxidative stress [14]
Low intensity oxidative stress
Intermediate intensity oxidative stress
High intensity oxidative stress

Supplementary resource (1)

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... However, the reactive oxygen species (ROS) such as singlet oxygen ( 1 O 2 ) generated in SDT may have limited efficacy [20]. Anti-ROS components such as antioxidant enzymes and small-molecule antioxidant compounds in vivo could counterbalance the increased ROS [21], while the effective distance and duration time of ROS are relatively short within the cellular milieu [22]. Furthermore, the adequate drug delivery in pancreatic cancer is hindered by relatively poor blood perfusion and dense stroma. ...
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... Oxidative stress was defined as an imbalance between oxidative and anti-oxidative systems, causing an impairment of redox signaling [11,12], which was closely related to obesity and its associated disorders [13]. Both obese patients and mice possessed lower antioxidant capacity than normal control [14,15]. ...
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Various fruits, vegetables, cereal grains, edible macrofungi, microalgae, and medicinal plants are containing phytoconstituents which are considered to be antioxidants. Polyphenols and carotenoids are the two main kinds of antioxidant phytochemicals and they contribute the most to the antioxidant properties of plant and its derivatives are widely employed as antioxidants. Turmeric is a rhizomatous herbaceous perennial plant (Curcuma longa) of the ginger family. The medicinal properties of turmeric, the source of curcumin, have been known for thousands of years; however, the ability to determine the exact mechanism(s) of action and to determine the bioactive components have only recently been investigated. Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), also called diferuloylmethane, is the main natural polyphenol found in the rhizome of Curcuma longa (turmeric) and in others Curcuma spp. Curcumin, a polyphenol, has been shown to target multiple signaling molecules while also demonstrating activity at the cellular level, which has helped to support its multiple health benefits such as antioxidant, anti-inflammatory, antimutagenic, antimicrobial and anticancer properties. Curcumin has received worldwide attention for its multiple health benefits, which appear to act primarily through its anti-oxidant and anti-inflammatory mechanisms.
Cardiovascular disease (CVD) is a broad term that incorporated a group of conditions that affect the blood vessels and the heart. CVD is a foremost cause of fatalities around the world. Multiple pathophysiological mechanisms are involved in CVD; however, oxidative stress plays a vital role in generating reactive oxygen species (ROS). Oxidative stress occurs when the concentration of oxidants exceeds the potency of antioxidants within the body while producing reactive nitrogen species (RNS). ROS generated by oxidative stress disrupts cell signaling, DNA damage, lipids, and proteins, thereby resulting in inflammation and apoptosis. Mitochondria is the primary source of ROS production within cells. Increased ROS production reduces nitric oxide (NO) bioavailability, which elevates vasoconstriction within the arteries and contributes to the development of hypertension. ROS production has also been linked to the development of atherosclerotic plaque. Antioxidants can decrease oxidative stress in the body; however, various therapeutic drugs have been designed to treat oxidative stress damage due to CVD. The present review provides a detailed narrative of the oxidative stress and ROS generation with a primary focus on the oxidative stress biomarker and its association with CVD. We have also discussed the complex relationship between inflammation and endothelial dysfunction in CVD as well as oxidative stress-induced obesity in CVD. Finally, we discussed the role of antioxidants in reducing oxidative stress in CVD.
De nos jours, les pathologies cardiovasculaires représentent un enjeu de santé publique majeur dans les pays développés. Particulièrement, le remodelage ventriculaire gauche touche 30% des patients suite à un infarctus du myocarde et peut mener à terme à une insuffisance cardiaque. Le remodelage et l’insuffisance cardiaque sont associés au développement d’un stress oxydant, participant aux modifications structurales et fonctionnelles du coeur. L’objectif de ma thèse consistait en l’étude des modifications post-traductionnelles de la protéine anti-oxydante mitochondriale superoxyde dismutase 2 (SOD2), et plus particulièrement de son inactivation par acétylation, dans le contexte des pathologies cardiovasculaires.J’ai montré que l’inactivation de SOD2 par acétylation de la lysine 68 favorise le stress oxydant et la dysfonction mitochondriale. Parmi les différents isoformes SIRT, la protéine mitochondriale SIRT3 a été identifiée comme responsable de l’activation de SOD2 par désacétylation, tandis que la protéine acetyl transferase P300 serait impliquée dans la régulation transcriptionnelle de SOD2. J’ai également montré que la protéine SIRT3 protège les cardiomyocytes du stress oxydant et de l’hypertrophie induite par stimulation à l’isoprénaline en activant la protéine SOD2. Ces données m’ont permis d’identifier la protéine SOD2 comme cible moléculaire potentielle dans les stratégies thérapeutiques anti-oxydantes.J’ai donc étudié l’impact des anti-oxydants MitoQuinone (MitoQ, antioxydant mitochondrial) et EUK 134 (mimétique des SOD) sur les cardiomyocytes et montré les effets protecteurs de la MitoQ et du EUK 134 sur le stress oxydant et l’hypertrophie. Cependant, la MitoQ entraîne des dysfonctions mitochondriales et un arrêt de la mitophagie délétères pour les cardiomyocytes, contrairement au EUK 134 qui permet de restaurer la fonction mitochondriale en maintenant l’équilibre de la mitophagie. Ces données mettent en évidence le rôle primordial du métabolisme mitochondrial dans le développement des thérapies anti-oxydantes.
Non-alcoholic steatohepatitis (NASH) represents a global health concern. It is characterised by fatty liver, hepatocyte cell death and inflammation, which are associated with lipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, iron overload and oxidative stress. NF-E2 p45-related factor 2 (Nrf2) is a transcription factor that combats oxidative stress. Remarkably, Nrf2 is downregulated during the development of NASH, which probably accelerates disease, whereas in pre-clinical studies the upregulation of Nrf2 inhibits NASH. We now review the scientific literature that proposes Nrf2 downregulation during NASH involves its increased ubiquitylation and proteasomal degradation, mediated by Kelch-like ECH-associated protein 1 (Keap1) and/or β-transducin repeat-containing protein (β-TrCP) and/or HMG-CoA reductase degradation protein 1 (Hrd1, also called synoviolin (SYVN1)). Additionally, downregulation of Nrf2-mediated transcription during NASH may involve diminished recruitment of coactivators by Nrf2, due to increased levels of activating transcription factor 3 (ATF3) and nuclear factor-kappaB (NF-κB) p65, or competition for promoter binding due to upregulation of BTB and CNC homology 1 (Bach1). Many processes that downregulate Nrf2 are triggered by transforming growth factor-beta (TGF-β), with oxidative stress amplifying its signalling. Oxidative stress may also increase suppression of Nrf2 by β-TrCP through facilitating formation of the DSGIS-containing phosphodegron in Nrf2 by glycogen synthase kinase-3. In animal models, knockout of Nrf2 increases susceptibility to NASH, while pharmacological activation of Nrf2 by inducing agents that target Keap1 inhibits development of NASH. These inducing agents probably counter Nrf2 downregulation affected by β-TrCP, Hrd1/SYVN1, ATF3, NF-κB p65 and Bach1, by suppressing oxidative stress. Activation of Nrf2 is also likely to inhibit NASH by ameliorating lipotoxicity, inflammation, ER stress and iron overload. Crucially, pharmacological activation of Nrf2 in mice in which NASH has already been established supresses liver steatosis and inflammation. There is therefore compelling evidence that pharmacological activation of Nrf2 provides a comprehensive multipronged strategy to treat NASH.
Spinal cord injury (SCI) is a central nervous system trauma that can cause severe neurological impairment. A series of pathological and physiological changes after SCI (e.g., inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction) promotes further deterioration of the microenvironment at the site of injury, leading to aggravation of neurological function. The multifunctional transcription factor NF-E2 related factor 2 (Nrf2) has long been considered a key factor in antioxidant stress. Therefore, Nrf2 may be an ideal therapeutic target for SCI. A comprehensive understanding of the function and regulatory mechanism of Nrf2 in the pathophysiology of SCI will aid in the development of targeted therapeutic strategies for SCI. This review discusses the roles of Nrf2 in SCI, with the aim of aiding in further elucidation of SCI pathophysiology and in efforts to provide Nrf2-targeted strategies for the treatment of SCI.
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Rheumatoid arthritis (RA) is an inflammatory disease that begins with a loss of tolerance to modified self-antigens and immune system abnormalities, eventually leading to synovitis and bone and cartilage degradation. Reactive oxygen species (ROS) are commonly used as destructive or modifying agents of cellular components or they act as signaling molecules in the immune system. During the development of RA, a hypoxic and inflammatory situation in the synovium maintains ROS generation, which can be sustained by increased DNA damage and malfunctioning mitochondria in a feedback loop. Oxidative stress caused by abundant ROS production has also been shown to be associated with synovitis in RA. The goal of this review is to examine the functions of ROS and related molecular mechanisms in diverse cells in the synovial microenvironment of RA. The strategies relying on regulating ROS to treat RA are also reviewed.
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Viral and bacterial infections are often associated with deficiencies in macronutrients and micronutrients, including the essential trace element selenium. In selenium deficiency, benign strains of Coxsackie and influenza viruses can mutate to highly pathogenic strains. Dietary supplementation to provide adequate or supranutritional selenium supply has been proposed to confer health benefits for patients suffering from some viral diseases, most notably with respect to HIV and influenza A virus (IAV) infections. In addition, selenium-containing multimicronutrient supplements improved several clinical and lifestyle variables in patients coinfected with HIV and Mycobacterium tuberculosis. Selenium status may affect the function of cells of both adaptive and innate immunity. Supranutritional selenium promotes proliferation and favors differentiation of naive CD4-positive T lymphocytes toward T helper 1 cells, thus supporting the acute cellular immune response, whereas excessive activation of the immune system and ensuing host tissue damage are counteracted through directing macrophages toward the M2 phenotype. This review provides an up-to-date overview on selenium in infectious diseases caused by viruses (e.g., HIV, IAV, hepatitis C virus, poliovirus, West Nile virus) and bacteria (e.g., M. tuberculosis, Helicobacter pylori). Data from epidemiologic studies and intervention trials, with selenium alone or in combination with other micronutrients, and animal experiments are discussed against the background of dietary selenium requirements to alter immune functions. © 2015 American Society for Nutrition.
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In reply to internal or external danger stimuli, the body orchestrates an inflammatory response. The endogenous triggers of this process are the damage-associated molecular patterns (DAMPs). DAMPs represent a heterogeneous group of molecules that draw their origin either from inside the various compartments of the cell or from the extracellular space. Following interaction with pattern recognition receptors in cross-talk with various non-immune receptors, DAMPs determine the downstream signaling outcome of septic and aseptic inflammatory responses. In this review, the diverse nature, structural characteristics, and signaling pathways elicited by DAMPs will be critically evaluated.
Oxidative stress pervades the chemical, biological, biochemical, and clinical-medical literature. The apparently simple concept of an imbalance between oxidants and antioxidants, potentially leading to molecular damage, has evolved in recent years to focus on biological responses, including a disruption of redox signaling and control. Related terms such as dietary oxidative stress, postprandial oxidative stress, physiological oxidative stress, photooxidative stress, radiation-induced oxidative stress, oxidant stress, pro-oxidant stress, and oxidative stress status are presented. Also, reductive stress and nitrosative stress are addressed.
The OxyR transcription factor is sensitive to oxidation and activates the expression of antioxidant genes in response to hydrogen peroxide in Escherichia coli. Genetic and biochemical studies revealed that OxyR is activated through the formation of a disulfide bond and is deactivated by enzymatic reduction with glutaredoxin 1 (Grx1). The gene encoding Grx1 is regulated by OxyR, thus providing a mechanism for autoregulation. The redox potential of OxyR was determined to be –185 millivolts, ensuring that OxyR is reduced in the absence of stress. These results represent an example of redox signaling through disulfide bond formation and reduction.
Reactive oxygen species (ROS) initially considered as only damaging agents in living organisms further were found to play positive roles also. This paper describes ROS homeostasis, principles of their investigation and technical approaches to investigate ROS-related processes. Especial attention is paid to complications related to experimental documentation of these processes, their diversity, spatiotemporal distribution, relationships with physiological state of the organisms. Imbalance between ROS generation and elimination in favor of the first with certain consequences for cell physiology has been called “oxidative stress”. Although almost 30 years passed since the first definition of oxidative stress was introduced by Helmut Sies, to date we have no accepted classification of oxidative stress. In order to fill up this gape here classification of oxidative stress based on its intensity is proposed. Due to that oxidative stress may be classified as basal oxidative stress (BOS), low intensity oxidative stress (LOS), intermediate intensity oxidative stress (IOS), and high intensity oxidative stress (HOS). Another classification of potential interest may differentiate three categories such as mild oxidative stress (MOS), temperate oxidative stress (TOS), and finally severe (strong) oxidative stress (SOS). Perspective directions of investigations in the field include development of sophisticated classification of oxidative stresses, accurate identification of cellular ROS targets and their arranged responses to ROS influence, real in situ functions and operation of so-called “antioxidants”, intracellular spatiotemporal distribution and effects of ROS, deciphering of molecular mechanisms responsible for cellular response to ROS attacks, and ROS involvement in realization of normal cellular functions in cellular homeostasis.
Exposure of cells to reactive oxygen species (ROS) causes a rapid and significant drop in intracellular ATP levels. This energy depletion negatively affects ATP-dependent chaperone systems, making ROS-mediated protein unfolding and aggregation a potentially very challenging problem. Here we show that Get3, a protein involved in ATP-dependent targeting of tail-anchored (TA) proteins under nonstress conditions, turns into an effective ATP-independent chaperone when oxidized. Activation of Get3's chaperone function, which is a fully reversible process, involves disulfide bond formation, metal release, and its conversion into distinct, higher oligomeric structures. Mutational studies demonstrate that the chaperone activity of Get3 is functionally distinct from and likely mutually exclusive with its targeting function, and responsible for the oxidative stress-sensitive phenotype that has long been noted for yeast cells lacking functional Get3. These results provide convincing evidence that Get3 functions as a redox-regulated chaperone, effectively protecting eukaryotic cells against oxidative protein damage.