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Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology

Nature Reviews Molecular Cell Biology volume 23, pages 499–515 (2022)Cite this article

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Abstract

‘Reactive oxygen species’ (ROS) is a generic term that defines a wide variety of oxidant molecules with vastly different properties and biological functions that range from signalling to causing cell damage. Consequently, the description of oxidants needs to be chemically precise to translate research on their biological effects into therapeutic benefit in redox medicine. This Expert Recommendation article pinpoints key issues associated with identifying the physiological roles of oxidants, focusing on H2O2 and O2.–. The generic term ROS should not be used to describe specific molecular agents. We also advocate for greater precision in measurement of H2O2, O2.– and other oxidants, along with more specific identification of their signalling targets. Future work should also consider inter-organellar communication and the interactions of redox-sensitive signalling targets within organs and whole organisms, including the contribution of environmental exposures. To achieve these goals, development of tools that enable site-specific and real-time detection and quantification of individual oxidants in cells and model organisms are needed. We also stress that physiological O2 levels should be maintained in cell culture to better mimic in vivo redox reactions associated with specific cell types. Use of precise definitions and analytical tools will help harmonize research among the many scientific disciplines working on the common goal of understanding redox biology.

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Fig. 1: Generation of superoxide and hydrogen peroxide and their relation to redox signalling.
Fig. 2: Redox interactome of hydrogen peroxide and superoxide.

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Acknowledgements

Generous support is acknowledged: G.E.M., British Heart Foundation (FS19/25/34277, FS16/67/32548), Heart Research UK (RG2672) and King’s Together Strategic Award; M.J.D., Novo Nordisk Foundation (Laureate grants NNF13OC0004294 and NNF20SA0064214); D.P.J., P30-ES019776, R21-ES031824, R01-ES023485, U2C-ES030163 and RC2-DK118619; M.P.M., Medical Research Council UK (MC_U105663142) and a Wellcome Trust Investigator Award (110159/A/15Z); V.V.B., Ministry of Science and Higher Education, Russian Federation (grant 075-15-2019-1789); and H.S., Deutsche Forschungsgemeinschaft, National Foundation for Cancer Research.

Author information

Authors and Affiliations

  1. Institute for Biochemistry and Molecular Biology I, Faculty of Medicine, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

    Helmut Sies

  2. Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany

    Helmut Sies

  3. Federal Center of Brain Research and Neurotechnologies, Federal Medical Biological Agency, Moscow, Russia

    Vsevolod V. Belousov

  4. Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia

    Vsevolod V. Belousov

  5. Division of Pulmonary & Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Navdeep S. Chandel

  6. Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark

    Michael J. Davies

  7. Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, USA

    Dean P. Jones

  8. King’s British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King’s College London, London, UK

    Giovanni E. Mann

  9. MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK

    Michael P. Murphy

  10. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

    Masayuki Yamamoto

  11. Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand

    Christine Winterbourn

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  1. Helmut Sies
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  2. Vsevolod V. Belousov
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  3. Navdeep S. Chandel
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  4. Michael J. Davies
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  9. Christine Winterbourn
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The authors contributed equally to all aspects of the article.

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Correspondence to Helmut Sies.

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Glossary

Electrophile

A molecule with an electron-deficient centre that reacts with electron-rich (nucleophile) species.

Redox tone

The oxidation–reduction steady states of redox-active elements in cells and tissues.

Radical

An atom or molecule with one or more unpaired electrons.

Redox medicine

The use of concepts and strategies of redox biology for applications in diagnosis and therapy.

Redox relay mechanisms

Mechanisms by which interacting molecules (often proteins) undergo reversible and consecutive redox reactions, transferring a redox signal from one site to another.

Peroxiredoxins

A family of six ubiquitous, highly reactive, thiol-containing enzymes that control hydrogen peroxide (H2O2) levels and mediate signal transduction.

Transition metal ion

A metal ion from the central block of the periodic table.

Fe–S cluster

Geometrical clusters of iron and sulfur. These occur in multiple forms including [2Fe–2S], [4Fe–3S], [3Fe–4S] and [4Fe–4S] and are often involved in electron transfer chains.

Uncoupling protein 1

(UCP1). A protein of the inner mitochondrial membrane that dissipates the proton electrochemical potential gradient across the membrane, thereby uncoupling oxidation from ATP production, leading to thermogenesis.

Superoxide dismutases

Enzymes which convert two molecules of superoxide (O2.–) to one molecule of oxygen and one molecule of hydrogen peroxide (H2O2), a process called dismutation.

Redox networks

Networks of interacting molecules that undergo redox reactions.

NADPH oxidases

(NOXs). Membrane-bound enzyme complexes, assembled from multiple protein components, that use NADPH to reduce O2 to the superoxide anion radical (O2.–) and/or hydrogen peroxide (H2O2).

Caveolae

Invaginations of the plasma membrane that bud off internally, which are thought to form from lipid rafts.

Ischaemia

A condition in which blood flow (and hence the supply of O2 and other materials) to a tissue is impaired.

Reverse electron transfer

Flow of electrons through an electron transport chain (ETC) in the reverse direction to that which normally occurs, for example in ischaemia.

Glutathione

(GSH). A key cysteine-containing tripeptide (γ-glutamyl-cysteine-glycine) that acts as a reducing cofactor and direct antioxidant.

Catalase

A haeme-containing protein that enzymatically dismutates hydrogen peroxide (H2O2) to O2 and H2O (catalatic reaction) or reduces H2O2 to H2O by oxidizing a hydrogen donor AH2 to A (peroxidatic reaction).

Xenobiotics

Chemical substances not naturally present in an organism.

Peroxiporin

An aquaporin that transports hydrogen peroxide (H2O2) across membranes.

Membrane contact sites

A location where membranes come into close proximity, facilitating transfer of molecules and signals.

Protein disulfide isomerase

(PDI). An enzyme typically, but not exclusively, found in the endoplasmic reticulum of eukaryotes that catalyses the formation and breakage of disulfide bonds between cysteine residues.

Thioredoxin

(TRX). A small ubiquitous redox-active protein that plays a role in redox signalling via the maintenance of cysteine residues in their thiol form.

Redox interactome

A collective term for all of the layers of omics space with redox interactions. This includes both reversible and irreversible redox reactions. The proteome has the largest number of reversible oxidizable elements.

Redox hubs

Central nodes in a redox network through which redox changes can impact multiple downstream components.

Selenocysteine

A selenium analogue of cysteine, where selenium replaces sulfur.

Fenton reaction

The reaction of Fe2+ with H2O2 that generates the hydroxyl radical (HO.).

Hormesis

A biologic process in which low-dose exposure to a stressor activates mechanisms that protect against future toxic exposures.

Transient receptor potential channels

A group of ion channels mostly localized on the plasma membrane of animal cells, mediating various sensations such as pain or temperature.

Myeloperoxidase

A leukocyte (mainly neutrophil and monocyte)-derived haeme enzyme that catalyses the conversion of hydrogen peroxide (H2O2) to multiple reactive oxidant species including hypochlorous acid (HOCl). A major component of the innate immune response against invading pathogens, but also strongly implicated in tissue damage at sites of inflammation.

Epiproteome

The set of post-translational modifications of the proteome supported by evolved mechanisms for control of protein activities. These are distinct from post-translational modification by reactive environmental chemicals. Many of these modifications, such as phosphorylation, are reversible and are integrated with redox systems in the redox interactome.

Oxystat

A device to maintain a constant O2 concentration despite fluctuations in the O2 consumption rate. These generally operate by having an O2 sensor and feedback system to regulate the rate of introduction of O2.

Boronates

A family of compounds derived from boric acid of general structure [R–B(OH)2], where R is an alkyl or aryl group. The hydroxyl groups can be derivatized to esters [R–B(OR′)2] to form redox-active probes.

Cytochrome c

A small (~12 kDa) haeme protein usually found loosely associated with the outer face of the inner mitochondrial membrane where it functions to transfer electrons between complex III and complex IV of the electron transport chain (ETC) via cycling between the Fe3+ and Fe2+ states. Its release into the cytosol is commonly used as a marker of mitochondrial damage and apoptosis.

Tetrazolium salts

Salts (including MTT, XTT, MTS and WSTs) with a tetra-nitrogen heterocycle that are reduced by the superoxide anion radical (O2.–) and also act as substrates for active cellular dehydrogenases and reductases. In the presence of NADH/NADPH, they are reduced to formazans which have strong, distinct optical absorption spectra. Widely used as a means of distinguishing metabolically active from inactive (dead) cells.

Lucigenin

An organic compound (10,10′-dimethyl-9,9′-bisacridinium nitrate) used, often inappropriately, as a chemiluminescent probe for the detection of superoxide anion radical (O2.–) in cells and tissue.

Luciferin

A small-molecule substrate for the enzyme luciferase that reacts with oxygen to release energy as light.

l-NAME

The l isomer of NG-nitro-arginine methyl ester, which is used as an inhibitor of nitric oxide synthase enzymes.

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Sies, H., Belousov, V.V., Chandel, N.S. et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat Rev Mol Cell Biol 23, 499–515 (2022). https://doi.org/10.1038/s41580-022-00456-z

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