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Cellular mechanisms and physiological consequences of redox-dependent signalling

Nature Reviews Molecular Cell Biology volume 15, pages 411–421 (2014)Cite this article

Subjects

Key Points

  • Oxidants, such as hydrogen peroxide and superoxide anions, can damage cellular components when produced in large amounts. When reactive oxygen species (ROS) are produced at lower, regulated levels, they can function in a diverse array of signalling pathways.

  • Members of the NADPH oxidase (NOX) family are important generators of intracellular ROS and have an important role in reduction–oxidation (redox) signalling.

  • Most redox signalling occurs by the reversible oxidation and reduction of crucial reactive Cys residues. One example is the family of protein Tyr phosphatases, which can be transiently inactivated by oxidation of the catalytic Cys residue.

  • Although it is less well understood than NOX-generated ROS, mitochondrial ROS production seems to be regulated in some manner and can also modulate signalling pathways.

  • Oxidant signalling might be an ancient mode of signal transduction, as it is observed in both plants and animals. Increasing evidence indicates that redox signalling might have a crucial role in the immune response, stem cell biology, cancer and ageing.

Abstract

Reactive oxygen species (ROS), which were originally characterized in terms of their harmful effects on cells and invading microorganisms, are increasingly implicated in various cell fate decisions and signal transduction pathways. The mechanism involved in ROS-dependent signalling involves the reversible oxidation and reduction of specific amino acids, with crucial reactive Cys residues being the most frequent target. In this Review, we discuss the sources of ROS within cells and what is known regarding how intracellular oxidant levels are regulated. We further discuss the recent observations that reduction–oxidation (redox)-dependent regulation has a crucial role in an ever-widening range of biological activities — from immune function to stem cell self-renewal, and from tumorigenesis to ageing.

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Figure 1: Sites for the generation of reactive oxygen species in mitochondria.
Figure 2: Intracellular sources of reactive oxygen species.
Figure 3: Reactive oxygen species can function as mediators of intracellular signalling.
Figure 4: The reversible modulation of reactive Cys residues underlies redox-dependent signalling.
Figure 5: The potential beneficial and harmful roles of antioxidants in tumorigenesis.
Figure 6: The multiple ways in which oxidant signalling can affect cellular function.

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Acknowledgements

The authors are grateful to members of the Finkel laboratory for helpful comments and to I. Rovira for help in preparing the manuscript. This work was supported by US National Institutes of Health (NIH) Intramural Funds and The Leducq Foundation.

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  1. Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Kira M. Holmström & Toren Finkel

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  1. Kira M. Holmström
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  2. Toren Finkel
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Correspondence to Toren Finkel.

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The authors declare no competing financial interests.

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Glossary

Complex IV

Together with complexes I–III, a series of large multisubunit protein complexes that are located on the inner mitochondrial membrane. They facilitate the flow of electrons that are initially extracted from substrates such as NADH. The energy that is obtained from the flow of these electrons is used to produce a proton gradient across the inner mitochondrial membrane, which facilitates ATP production.

Proton-motive force

The combination of the electrical and chemical pH gradients across the inner mitochondrial membrane.

Neutrophils

The most abundant type of circulating white blood cell. This phagocytic cell type can engulf and kill a bacterium through the generation of reactive oxygen species.

Chronic granulomatous disease

A rare genetic disease that is characterized by recurring infections. The molecular defect is the inability to generate reactive oxygen species owing to inherited mutations in the NADPH oxidase that are found in immune cells.

Respiratory burst

The rapid, high level release of reactive oxygen species (ROS) following the activation of an immune cell.

Cytochrome P450 enzymes

A large family of related proteins that function as monooxygenases and metabolize a wide range of substances, including steroids, lipids, xenobiotics and toxins.

Peroxisome

A subcellular organelle that is involved in the metabolism of very long-chain fatty acids and branched-chain fatty acids. Shorter fatty acids are metabolized in mitochondria.

Toll-like receptors

(TLRs). Single-pass transmembrane receptors that have a crucial role in innate immunity. Lipopolysaccharide (LPS) is one of many ligands for members of this receptor family.

Retinoic acid-inducible gene I signalling

(RIG-I signalling). A pathway that regulates the cellular response to viral infection on the basis of the ability of RIG-I to directly bind double-stranded RNA.

Inflammasome

A large intracellular, multiprotein complex that has a crucial role in innate immunity. Once activated, the inflammasome leads to caspase 1 activation and the subsequent maturation of various inflammatory cytokines.

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Holmström, K., Finkel, T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 15, 411–421 (2014). https://doi.org/10.1038/nrm3801

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