Defining ROS in Biology and Medicine

Abstract

Utilization of molecular oxygen by aerobic organisms inevitably results in the formation of a number of oxygen-containing reactive species that are collectively known as reactive oxygen species (ROS). ROS play important roles in both physiology and pathophysiology of aerobic life. The field of 'ROS biology and medicine' deals with the involvement of ROS and related species in contemporary biology and medicine. The purpose of this article is to survey common terms and concepts in ROS biology and medicine. It also introduces the 'ROS paradigm' so as to provide a conceptual framework for understanding the rapidly evolving field of ROS biology and medicine.

Keywords: Oxidative stress; ROS paradigm; Reactive oxygen species; Redox signaling.

FIGURE 1. Excitation and univalent reduction of molecular oxygen to yield reactive oxygen species (ROS) in biological systems

As indicated, ground state molecular oxygen (O₂) is a free radical (actually a di-radical) because it contains two unpaired electrons. O₂ is much less reactive than ROS due to spin restriction caused by the same spin direction of its two unpaired electrons. O₂ can be excited to form singlet oxygen (¹O₂). There are two states of singlet oxygen: delta and sigma. The sigma state singlet oxygen is a free radical, whereas the delta state is a non-radical. One electron reduction of O₂ gives rise to superoxide anion radical (O₂^▪−), which then undergoes another one electron reduction to yield hydrogen peroxide (H₂O₂). One electron reduction of hydrogen peroxide generates hydroxyl radical (OH^▪), which can then be reduced by one electron to form water. Perhydroxyl radical (HO₂^▪) is a protonated form of superoxide anion radical.

FIGURE 2. Schematic illustration of oxidative stress

As depicted, oxidative stress is caused by either increased formation of reactive oxygen species (ROS) or decreased antioxidant defenses, or both. It is important to distinguish oxidative stress from redox signaling. Oxidative stress emphasizes the potential detrimental effects of increased ROS, whereas redox signaling underlines the involvement of ROS in cell signaling transduction leading to physiological responses.

FIGURE 3. The three major steps of cell signaling

This scheme illustrates the three major steps involved in cell signal transduction upon extracellular stimulation. The extracellular stimulus (signaling molecule) can be a growth factor that acts on the target cell to cause a physiological cellular response (e.g., cell proliferation). The entire signal transduction process consists of three major steps: (i) binding of the extracellular signaling molecule to its receptor embedded in the plasma membrane of the target cell, leading to receptor activation; (ii) the activated receptor in turn either directly or indirectly (via formation of second messengers, such as cyclic AMP) causes activation of the signaling molecules (typically proteins) of one or more of the signal transduction pathways; and finally (iii) one or more of the activated signaling proteins alter the activity of effector proteins that reside at the end of signaling pathways and thereby the behavior of the cell.

FIGURE 4. Components of reactive oxygen species (ROS)-mediated redox signaling

ROS- mediated cellular redox signaling involves multiple components. The generators are cellular processes (e.g., mitochondrial respiration and activation of NAD(P)H oxidases) responsible for the controlled production of the ROS, whereas the terminators (e.g., antioxidants) act to scavenge or inactivate the ROS so that the formation and disappearance of the ROS occur in a regulated manner. The sensor molecules (e.g., protein kinases, transcription factors, or other proteins) sense the ROS-induced changes of the cellular redox milieu chemically by undergoing oxidation and reduction reactions. Such redox reactions modulate the functions or conformations of the sensors, altering activities of downstream effectors, leading to cellular responses. Also see text (Section 5.3) for additional description.

FIGURE 5. The ROS paradigm

This paradigm defines the scope of ROS biology and medicine which includes generation of ROS and related reactive species, the interactions of these reactive species with target biomolecules, and the resulting biological consequences (adverse or beneficial). This paradigm also depicts the antioxidant-based intervention of diseases associated with ROS, emphasizing the importance of selectively controlling ROS-mediated adverse effects without compromising the physiological functions of these species.