Oxidant signals and oxidative stress

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Abstract

Although oxidants clearly possess the capacity to behave in a random and destructive fashion, growing evidence suggests that in many instances the production of reactive oxygen species is tightly regulated and their downstream targets exquisitely specific. This past year, several notable advances have been made in defining the specific redox-dependent targets of intracellular oxidants, as well as the myriad pathways that appear to employ oxidants as effector molecules. These new studies have significantly altered our understanding of how reactive oxygen species participate in diverse processes from tumourigenesis to ageing.

Introduction

Studies over the past few years have demonstrated that reactive oxygen species (ROS) actively participate in a diverse array of biological processes, including normal cell growth, induction and maintenance of the transformed state, programmed cell death and cellular senescence. How, then, can a seemingly simple rise in ROS trigger such divergent responses? One explanation might be that these different biological outcomes reflect subtle differences in the level and duration of the oxidant burst or the cellular context that accompanies this oxidative stress. Although such qualitative or quantitative arguments might explain part of the biological variation, these observations also highlight the current limitations of our understanding. Similarly, in many cases it still remains unclear whether the observed alteration in the redox state is the cause or merely the consequence of the subsequent cellular events.

In this review, I will focus on progress made primarily in the past year in the understanding of sources and targets of intracellular ROS, as well as the various normal and pathological states that appear to be associated with active cellular redox regulation.

Section snippets

Oxidases: new and old

Oxidants can be produced within cells by multiple enzymes that use molecular oxygen as a substrate. Two classic phagocytic ROS-generating enzymes, the multisubunit NADPH oxidase and myeloperoxidase (MPO), were first studied because of their essential role in host defence. Oxygen radicals and other toxic species produced by the NADPH oxidase and MPO were thought to be directly responsible for killing microorganisms; however, new evidence suggests that it is the release of proteases from within

Oxidant signalling

Previous studies have demonstrated that receptor binding of numerous peptide growth factors stimulate ROS production and that this oxidant burst is required for certain aspects of downstream signalling [8]. Several recent examples extend these findings to include a role for oxidants in insulin [9] and vascular endothelial growth factor (VEGF) signalling [10]. Signalling of cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) also leads to oxidant production; and the

Oxidants, stress and ageing

One of the most intriguing aspects of the growing appreciation of ROS and their role in normal cell signalling is the ability to revisit the role of oxidants in disease processes. A variety of evidence suggests that oxidants participate in normal ageing and in age-related disease maladies such as cancer, atherosclerosis and neurodegeneration [25]. Recent evidence has further tightened the association between the cellular response to oxidants and the mechanisms that regulate longevity. For

Oncogenes and oxidants

It has been appreciated for some time that transformed cells produce elevated levels of ROS, including hydrogen peroxide [42]. Nonetheless, the interrelationship between ROS and cellular transformation has been extensively re-evaluated recently. One of the hallmarks of transformation is genomic instability, and — at least for cells in culture — it now appears that the degree of spontaneous chromosomal breakage is directly related to cellular oxygen tension [43]. Another hallmark of transformed

Anti-oxidant networks

A variety of proteins function as scavengers of superoxide and hydrogen peroxide. These include, among others, SOD, catalase, glutathione peroxidase, thioredoxin, and the peroxiredoxin family of proteins. These protein antioxidants are supplemented with a host of nonprotein scavengers, including, but not limited to, intracellular ascorbate and glutathione. In general, these enzymatic and nonenzymatic scavengers have been viewed as independent means of eliminating the oxidant burden. Two new

Omics and oxidative stress

Several recent studies conducted on a wide range of species have employed a genomics or proteomic approach to begin to unravel a more complete picture of the cellular responses to oxidative stress. To summarise many of these reports, it would appear that gene products linked to ROS metabolism are one class of genes that are consistently induced following oxidative stress. These same sets of genes are also often upregulated in simple organisms such as yeast when there is a shift in metabolic

Conclusions

Changes in the intracellular redox state appear to regulate several critical intracellular pathways. There is a growing appreciation that for several enzymatic sources of ROS generation, radical generation is not a useless or harmful by-product of enzymatic activity, but rather, an essential element required for the intended biological responses. In addition, there appears to be a subset of protein targets within the cell that can alter their function following either local or global redox

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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    of special interest

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    of outstanding interest

Acknowledgements

I am grateful for the efforts and useful comments from members of my laboratory, and in particular the assistance of Ilsa Rovira. I apologise to my colleagues in advance for the omission of some important studies that, because of space limitations, I could not include.

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