Oxidative stress concept updated: Definitions, classifications, and regulatory pathways implicated

Abstract

Reactive oxygen species were discovered in living organisms in the early 1950's and their action has been implicated in diverse biological processes. First formulated by H. Sies in 1985[57], the oxidative stress concept stimulated substantial interest in reactive oxygen species and it is now common that fundamental research in various biomedical fields includes mention of research on the involvement of oxidative stress. Such strong interest has resulted in the development of definitions and classifications of oxidative stress and much research progress in the field. Although we clearly understand the limitations of various definitions or classifications, such parameters may help to provide quantitative descriptions, compare related processes among different laboratories, and introduce some measurable parameters. This paper highlights recent advances in the areas of oxidative stress definitions and the classification of oxidative stresses. Such items are directly associated with our understanding of the molecular mechanisms involved in organismal responses to oxidative insults. The knowledge accumulated to date indicates that selective expression of specific genes is a central player in the adaptive response to oxidative stress and reversible oxidation of cysteine residues of sensor proteins is a key process regulating responses to oxidative stress.

Keywords: Nrf2; OxyR; SoxRS; Yap1; adaptation; cysteine residues; reversible oxidation.

Figure 1. Schematic presentation of the time-course based classification of oxidative stresses. Usually a steady-state ROS concentration can be maintained within a certain range and fluctuates like other parameters in the body according to homeostasis theory. However, under certain circumstances, ROS concentration may exit from this corridor due to increased generation or decreased elimination of ROS. The situation when ROS levels increase for a short time period with certain functional consequences is called “acute oxidative stress”, whereas a prolonged increase in ROS levels accompanied by such consequences is called “chronic oxidative stress.” In some cases, ROS levels do not return into the original corridor or stabilize close to it and or even stabilize at a higher steady-state level, called a quasi-stationary state. Both acute and chronic oxidative stresses may affect living organisms differently and cause more or less significant damage to cells and, if the system is unable to regain control, can lead to cell death by apoptosis or necrosis. The reverse situation when steady-state ROS concentrations decrease relative to the initial level has been called “reductive stress” (modified from Lushchak, 2014b, under the CC BY 4.0 license).

Figure 2. Schematic presentation of the intensity-based classification of oxidative stresses. Curve 1 shows the path of a ROS-induced ROS-sensitive parameter (ROSISP), for example, the activity of an antioxidant enzyme, whereas curve 2 indicates the path of a ROS-modified cellular substance (ROMS), for example, oxidized lipids, proteins or nucleic acids. In fact, curves 1 and 2 show the relationship between the dose/concentration of the oxidative stress inducer and parameters typically used to characterize the stress and that can be experimentally measured. Region I - basal oxidative stress (BOS) is where there are no observable effects due to a very low intensity of oxidative stress; Region II - low intensity oxidative stress (LOS) with a slightly increased level of ROS-modified molecules and enhanced activity of antioxidant enzymes in response to oxidative stress; Region III - strong oxidative stress (SOS); and Region IV - very strong oxidative stress (VOS), where the values ​​of the recorded parameters reach nearly maximum/minimum values. Abbreviations: NOE - no observable effect point; ZEP - zero equivalent point where the levels of components of interest correspond to the initial (basic) level in the absence of an inducer of oxidative stress. (Modified from Lushchak, 2014b, under the CC BY 4.0 license).

Figure 3. Oxidative pattern of cysteine residues in proteins: sulfenic, sulfinic, or sulfonic derivatives and the possibilities for their reduction. In biological systems, organosulfur sulfenic and sulfinic derivatives may be reduced by thioredoxin and sulfiredoxin, respectively, whereas the sulfonic form is not reduced by these agents. Glutathionylated proteins are formed by direct interaction of GSH with sulfenic acid derivatives, exchange between cysteine residues and GSSG, or interaction with oxidized glutathione forms. Formation of S-nitrosothiols, containing a nitroso group attached to the sulfur atom of a thiol, may be the way of protecting thiol groups against oxidation and stabilization or transportation of unstable nitric oxide. Abbreviations: G6P - glucose-6-phosphate; 6PG - 6-phosphogluconate; GR - glutathione reductase; G6PDH - glucose-6-phosphate dehydrogenase