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Review
. 2014 May 19;24(10):R453-62.
doi: 10.1016/j.cub.2014.03.034.

ROS function in redox signaling and oxidative stress

Michael Schieber  1 , Navdeep S Chandel  2
Affiliations
Review

ROS function in redox signaling and oxidative stress

Michael Schieber et al. Curr Biol. .

Abstract

Oxidative stress refers to elevated intracellular levels of reactive oxygen species (ROS) that cause damage to lipids, proteins and DNA. Oxidative stress has been linked to a myriad of pathologies. However, elevated ROS also act as signaling molecules in the maintenance of physiological functions--a process termed redox biology. In this review we discuss the two faces of ROS--redox biology and oxidative stress--and their contribution to both physiological and pathological conditions. Redox biology involves a small increase in ROS levels that activates signaling pathways to initiate biological processes, while oxidative stress denotes high levels of ROS that result in damage to DNA, protein or lipids. Thus, the response to ROS displays hormesis, given that the opposite effect is observed at low levels compared with that seen at high levels. Here, we argue that redox biology, rather than oxidative stress, underlies physiological and pathological conditions.

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Figures

Figure 1
Figure 1. Basics of ROS
Intracellular superoxide (O2-) is primarily produced from the oxidation of NADPH by oxidase enzymes (NOX) or from electron leak from aerobic respiration in the mitochondria. Superoxide is rapidly converted into hydrogen peroxide (H2O2) by compartment-specific superoxide dismutases (SODs). H2O2 is capable of oxidizing cysteine residues on proteins to initiate redox signaling. Alternatively, H2O2 may be converted to H2O by cellular antioxidant proteins, such as peroxiredoxins (PRx), glutathione peroxidase (GPx), and catalase (CAT). When H2O2 levels increase uncontrollably, hydroxyl radicals (OH·) form through reactions with metal cations (Fe2+) and irreversibly damage cellular macromolecules
Figure 2
Figure 2. ROS regulation of normal and cancer cell proliferation
(A) Hydrogen peroxide (H2O2) is required for activation of a number of cellular pathways involved in cellular proliferation. (B) Cancer cells generate higher levels of ROS that are essential for tumorigenesis. Genetic alterations leading to activation of oncogenes (PI3K, MAPK, HIFs, NF-κB) and loss of tumor suppressors (p53) coordinate an elevated redox state. ROS is also generated from increased oxidative metabolism and hypoxia in rapidly expanding tumors. Cancer cells also express elevated levels of cellular antioxidants (SODs, GSH, GPx, PRx) in part through NRF-2 to protect against oxidative stress-induced cell death.
Figure 3
Figure 3. ROS Regulation of Inflammation
(A) Activation of the innate immune system requires ROS signaling. Common features of pathogens and cell damage (PAMPs, DAMPs) activate surveillance receptors (TLR, NLR, RLR) which increase ROS through NAPDH oxidase enzymes and the mitochondria. ROS is required for release of pro-inflammatory cytokines (IL-1β, TNFα, IFNβ) for a proper immune response. (B) Low levels of ROS maintain a healthy immune system. Decreasing ROS levels inhibits activation of proper immune responses, leading to immunosuppression. Elevated ROS levels contribute to autoimmunity through increased release of pro-inflammatory cytokines and proliferation of specific subsets of adaptive immune cells.
Figure 4
Figure 4. ROS Regulation of Aging
(A) Moderate ROS levels are required for proper stem cell differentiation and renewal through activation of signaling pathways. On one hand, decreased ROS levels impair stem cell properties, but ROS levels that are too high lead to stem cell exhaustion and premature aging through activation of signaling pathways. (B) Increased ROS are not detrimental to lifespan. Activation of cellular responses due to slight increases in ROS can increase signaling pathways that counter the normal aging process. However, high ROS levels can hyper-activate signaling pathways that promote inflammation, cancer and cell death leading to an accelerated aging phenotype.
Figure 5
Figure 5. Janus of ROS: A Therapeutic Conundrum
Redox biology encompasses both the physiological and pathological roles of ROS. Determining whether to use prooxidant therapy to promote physiological ROS responses or antioxidant therapy to prevent ROS pathologies remains the central question in redox biology.
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