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Reactive oxygen species (ROS) as pleiotropic physiological signalling agents

Abstract

‘Reactive oxygen species’ (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as ‘oxidative distress’. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as ‘oxidative eustress’. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·−), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).

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Fig. 1: Estimated ranges of H2O2 concentration with regard to cellular responses: oxidative eustress and oxidative distress.
Fig. 2: Key modulators and targets of H2O2.
Fig. 3: Pleiotropy of redox signalling in cell biology.
Fig. 4: H2O2 drives different cellular outcomes depending on its concentrations.
Fig. 5: Prospects for redox medicine.

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Acknowledgements

The authors thank the many colleagues whose research work contributed to this rapidly expanding field, and we apologize to the many authors whose interesting work could not be referred to explicitly. Fruitful discussions with W. Stahl and C. Berndt are gratefully acknowledged. Generous research support was provided by the Deutsche Forschungsgemeinschaft, Bonn, and the US National Foundation for Cancer Research, Bethesda, to H.S. and by the US National Institutes of Health to D.P.J.

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Glossary

Pleiotropic

From Greek pleion, meaning ‘more’, and tropos, meaning ‘way’, in biology originally denoting that one gene can influence two or more seemingly unrelated phenotypic traits. In current usage, the term describes multiple actions exerted by a given agent. If the actions generate opposing effects (for example, both harmful and beneficial to an organism), it is antagonistic pleiotropy.

Redox signalling

Response of a cell to an oxidant or reductant, or to an alteration in redox status of a cellular component, that leads to a variety of downstream effects on cell state directly or via an essential redox relay from a source to a target.

Oxidative eustress

Term describing the physiological oxidative challenge (Greek eu, meaning ‘good’, ‘well’, ‘positive’), essential in redox signalling. Supraphysiological oxidative challenge is denoted as ‘oxidative distress’.

Thiolate

Anion formed from thiol by dissociation of a proton (RSH → RS + H+).

Selenoproteins

Proteins with selenocysteine, the 21st amino acid, in the primary structure. Selenomethionine can sometimes substitute for methionine during protein synthesis, but unlike selenocysteine, this is not encoded within the RNA message and is generally without functional significance.

Hormesis

From Greek hormesis ‘rapid motion, eagerness’, describing a biphasic dose-response phenomenon: low-dose exposure (stimulation, preconditioning) and high-dose exposure (inhibition), J-shaped or inverted U-shaped dose-response curve.

4-Hydroxynonenal

A reactive aldehyde produced during free radical chain reaction of polyunsaturated fatty acids.

Lipid peroxidation

Oxidative free radical chain reaction of polyunsaturated fatty acids.

Mitochondrial electron transport chain

(ETC). Series of electron transfer complexes in the mitochondrial inner membrane that support oxidation of metabolic fuels to generate an electrochemical proton gradient for ATP synthesis from ADP and inorganic phosphate. Complexes within this chain are also sources of O2·– and its product, H2O2.

Cristae

Folds of the mitochondrial inner membrane.

Peroxiredoxins

Enzymes that catalyse reduction of H2O2 with a thioredoxin as the electron donor.

Glutathione

Tripeptide (γ-glutamylcysteinylglycine) that is widespread in biology and, among other functions, supports antioxidant reactions.

Peroxidases

Enzymes which catalyse the reduction of H2O2 and other hydroperoxides.

Catalatic reaction

One of the modes of catalysis for catalase, along with peroxidatic reaction. In the overall reaction cycle, the intermediate formed by reaction of catalase haem iron with H2O2, termed ‘compound I’, can be reduced by a second molecule of H2O2 (catalatic reaction) or by an alternative hydrogen donor (peroxidatic reaction).

Thioredoxin system

A thiol antioxidant system consisting of NADPH, thioredoxin reductase and thioredoxin that supports maintenance of protein thiols and reduction of hydroperoxides.

Glutathione system

A thiol antioxidant system consisting of glutathione peroxidases, glutathione disulfide reductase, glutathione S-transferases, glutaredoxin, glutathione synthesis enzymes and glutathione which supports maintenance of protein thiols and reduction of hydroperoxides.

Iron–sulfur (Fe–S) clusters

Redox centres in proteins in which iron is coordinately bonded between cysteinyl residues (thiolates) in protein and sulfide (S2−), for example, Fe2S2 and Fe4S4.

Sirtuin family

Enzymes that remove acetyl (that is, functioning as deacetylases) or other acyl groups (that is, functioning as desuccinylases, demalonylases, demyristoylases or depalmitoylases) from proteins.

Autophagy

A process for removal of damaged cellular structures that contributes to maintenance of cellular homeostasis.

Glutathionylation

A post-translational protein modification functioning in redox signalling comprising the reversible formation of an S-glutathione adduct of a cysteinyl residue in proteins. Glutaredoxins are enzymes that catalyse the formation and removal of S-glutathionylated proteins.

Src kinase

A member of a family of non-receptor tyrosine kinases with many protein targets and functions in differentiation and regulation of cell growth.

Xanthine oxidase

A form of xanthine dehydrogenase that generates a relatively high proportion of O2·– instead of H2O2 during oxidation of hypoxanthine to xanthine or xanthine to uric acid.

Aconitase

An enzyme in the citric acid cycle that has an Fe–S cluster and is sensitive to inactivation by O2·–.

Mitochondrial permeability transition pore

A pore formed from structural changes in mitochondrial inner membrane proteins that allow influx of solutes into the mitochondrial matrix. Activation of the pore causes high-amplitude swelling of the mitochondria and activates cell death mechanisms.

Unfolded protein response

(UPR). A cell stress response triggered by disruption of protein processing within the endoplasmic reticulum.

ER stress

Perturbation of functions of the endoplasmic reticulum (ER), for example abnormal folding and processing of proteins.

Axonal growth cone

Site of growth at the tip of a dendrite or an axon of neurons, containing cytoplasm and actin formed in the leading edge of the cell during neuronal development and regeneration.

Cell senescence

A state of cells with arrested cell division and resistance to cell proliferation signals and uncontrolled cell growth. Accumulation of senescent cells is a hallmark of ageing; it contributes to decline in organ function and some age-related diseases.

Exosomes

Nanometre-sized vesicles released by cells, a means for cell–cell communication. Exosomes possess characteristics of cells of origin and can be used as biomarkers of disease.

Neutrophil extracellular traps

Extracellular fibre networks created by neutrophils to trap and kill invading microbes. They contain DNA from extruded chromatin and antimicrobial proteins such as neutrophil elastase and cathepsin G.

NLRP3 inflammasome

NLRP3 is protein complex in cells that activates inflammatory processes. ‘NLR’ refers to ‘nucleotide-binding oligomerization domain, leucine-rich repeat’. The complex senses a broad range of microbial and environmental stressors.

Schiff base

A chemical structure with a double bond between nitrogen and carbon formed by reaction of an amine with a carbonyl group.

Michael addition

An addition reaction of a nucleophilic chemical with a chemical having an electrophilic α,β-conjugated carbonyl structure. The reaction can be important in pathological processes because DNA and other macromolecules contain nucleophiles, and α,β-conjugated carbonyls are major products of lipid peroxidation of polyunsaturated fatty acids.

Redox cycling agents

Chemicals that undergo enzymatic one-electron reduction, generating a transient radical, which is reoxidized by molecular oxygen, reducing it to O2·–.

Photodynamic therapy

A therapy using photoexcitable agents and light to generate toxic reactive oxygen species, predominantly singlet molecular oxygen.

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Sies, H., Jones, D.P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 21, 363–383 (2020). https://doi.org/10.1038/s41580-020-0230-3

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