Principles in Redox Signaling: From Chemistry to Functional Significance

Abstract

Reactive oxygen and nitrogen species are currently considered not only harmful byproducts of aerobic respiration but also critical mediators of redox signaling. The molecules and the chemical principles sustaining the network of cellular redox regulated processes are described. Special emphasis is placed on hydrogen peroxide (H2O2), now considered as acting as a second messenger, and on sulfhydryl groups, which are the direct targets of the oxidant signal. Cysteine residues of some proteins, therefore, act as sensors of redox conditions and are oxidized in a reversible reaction. In particular, the formation of sulfenic acid and disulfide, the initial steps of thiol oxidation, are described in detail. The many cell pathways involved in reactive oxygen species formation are reported. Central to redox signaling processes are the glutathione and thioredoxin systems controlling H2O2 levels and, hence, the thiol/disulfide balance. Lastly, some of the most important redox-regulated processes involving specific enzymes and organelles are described. The redox signaling area of research is rapidly expanding, and future work will examine new pathways and clarify their importance in cellular pathophysiology. Antioxid. Redox Signal. 18, 1557–1593. I. Introduction A. Cell signaling and redox signaling B. ROS involved in redox signaling 1. Superoxide anion 2. H2O2 and hydroperoxides 3. Hydroxyl radical and singlet oxygen C. RNS involved in signaling processes II. Cellular Sources of ROS A. NADPH oxidase B. Mitochondria C. Peroxisomes D. Xanthine oxidase E. Sulfhydryl oxidases F. Other sources of ROS III. Protein Targets Sensitive to Oxidant Species A. Chemistry and biochemistry of thiol oxidation 1. Sulfenic acid a. Formation of sulfenic acid by reactions of thiols with peroxides b. Formation of sulfenic acids from sulfenyl halides c. Formation of sulfenic acid from nitrosothiols d. Reactions of sulfenic acid e. Sulfinic and sulfonic acids 2. Disulfides a. Formation and role of disulfide bonds in proteins b. Oxidation of disulfides IV. Control of Cellular Levels of Peroxides and the Thiol Redox Balance A. Thiol-dependent systems involved in cellular redox balance 1. The thioredoxin system: characteristics and functions 2. The thioredoxin system and redox-regulated processes 3. The glutathione system 4. Importance of the inhibition of thioredoxin and glutathione systems for cancer chemotherapy V. Redox-Regulated Systems and Their Role in Signaling Pathways A. Transcription factor OxyR: a classic example of redox signaling B. The Gpx3/Orp1-Yap1 system in yeast. Peroxidases may act as sensors of peroxides. C. Protein kinases and phosphatases: relationship between phosphorylation processes and redox signaling D. NF-κB: the first mammalian transcription factor shown to undergo redox regulation E. The Keap1-Nrf2-ARE pathway: redox signaling by nutritional phytochemicals F. Hypoxia-inducible factor-1: a critical modulator of oxygen homeostasis G. Ero1: Disulfide bond formation and maintenance of redox homeostasis in ER H. SOD: redox control I. Control of mitochondrial functions and redox regulation of permeability transition J. Endoplasmic and sarcoplasmic reticulum calcium movements: a link between redox signaling and calcium signaling VI. Conclusions