Review
From birth to death: A role for reactive oxygen species in neuronal development

https://doi.org/10.1016/j.semcdb.2017.09.012Get rights and content

Abstract

Historically, ROS have been considered toxic molecules, especially when their intracellular concentration reaches high values. However, physiological levels of ROS support crucial cellular processes, acting as second messengers able to regulate intrinsic signaling pathways. Specifically, both the central and peripheral nervous systems are especially susceptible to changes in the redox state, developing either a defense or adaptive response depending on the concentration, source and duration of the pro-oxidative stimuli. In this review, we summarize classical and modern concepts regarding ROS physiology, with an emphasis on the role of the NADPH oxidase (NOX) complex, the main enzymatic and regulated source of ROS in the nervous system. We discuss how ROS and redox state contribute to neurogenesis, polarization and maturation of neurons, providing a context for the spatio-temporal conditions in which ROS modulate neural fate, discriminating between “oxidative distress”, and “oxidative eustress”. Finally, we present a brief discussion about the “physiological range of ROS concentration”, and suggest that these values depend on several parameters, including cell type, developmental stage, and the source and type of pro-oxidative molecule.

Introduction

Reactive oxygen species (ROS) form a family of molecules derived from molecular oxygen (O2) present in the atmosphere. The most common ROS members are the superoxide anion (O2radical dot_), the hydroxyl radical (HOradical dot) and hydrogen peroxide (H2O2) [1]. Both superoxide anions and hydroxyl radicals are free radical molecules, with one electron missing from the atomic orbit of the oxygen molecule. In contrast, hydrogen peroxide is an electrically neutral molecule and is chemically more stable than the other ROS family members [2]. Altogether, ROS support the oxidative power of the eukaryotic cell, promoting important physiological functions, ranging from the innate immune response to neuronal development.

ROS are produced either enzymatically or non-enzymatically. The mitochondrion is one of the main sources of intracellular ROS, as a consequence of aerobic metabolism and ATP synthesis [1]. The contribution of mitochondria to the cellular concentration of ROS is notable, and several anti-oxidant systems within these organelles have been described in detail [3], [4], [5], [6]. In addition, enzymatic ROS synthesis, mainly sustained by the NADPH-oxidase (NOX) family proteins, contributes towards maintaining physiological ROS levels according to cellular demands [7]. In fact, a recently published study supports the notion that NOX enzymes are instrumental in sustaining almost 45% of intracellular hydrogen peroxide in cultured hippocampal neurons, showing the strong influence that NOX enzymes have on the redox state [8].

Most of the literature discusses the disadvantages and benefits of O2-dependent oxidation. Of note, molecular nitrogen (N2), the most abundant gas in the troposphere, also drives the synthesis of pro-oxidative molecules, collectively named Nitrogen Reactive Species (NRS) [9]. Both the nature and functions of NRS have been less explored than those of ROS. Nevertheless, it is very likely that the contribution of NRS to neuronal physiology is important, as N2 represents almost 78% of the air we breathe.

This review focuses on the neuronal effect of ROS synthesis mediated by the NOX complex, discussing their contribution to differentiation, development and regeneration of neurons of both the central and peripheral nervous systems.

In general terms, ROS have been considered for many years as toxic molecules, generated as unavoidable by-products of cellular metabolism [10], leading to the oxidation of cellular macromolecules such as membrane lipids, proteins and DNA [11]. ROS have been largely associated with oxidative distress, producing an imbalance between oxidative and reductive power, and thus modifying the redox status of the cell [2], [12]. The list of diseases linked to oxidative stress is vast and includes several types of cancer [13], atherosclerosis, diabetes [14], and neurological disorders [15], like Amyotrophic Lateral Sclerosis and Parkinson’s disease, among others [2]. Interestingly, many of these pathologies emerge with aging, which highlights the point that both oxidative stress and lifespan or health span may be connected, probably as a consequence of living in an aerobic environment. Undoubtedly, abnormally high and dysregulated ROS production leads to oxidative distress and cell death, but the regulation of ROS levels in response to cellular demands is critical for normal cell behavior.

Accumulating evidence suggests that ROS should be considered as second messengers involved in numerous signaling pathways in health and disease [9], [16], [17]. Indeed, ROS fulfill several criteria of second messenger molecules, such as a short life-time and the ability to amplify a cellular signal triggered by the primary ligand. In addition, ROS have the special attribute of “chemical interconversion” [18]. The superoxide anion derived from NOX enzymes is rapidly converted into hydrogen peroxide, either spontaneously or enzymatically by superoxide dismutase (SOD). In turn, hydrogen peroxide can be transformed into the hydroxyl radical via a non-enzymatic step called the “Fenton reaction”, which mostly depends on the availability of Fe2+ in the cytoplasm [19]. Another feature of ROS, consistent with their role as possible second messengers, is that the synthesis of superoxide anions and hydrogen peroxide (but not hydroxyl radicals) is finely regulated [20], [21], [22].

Section snippets

Structural and biochemical features of NOX enzymes

The main product of the NADPH-oxidase (NOX) enzymes is the superoxide anion. Nevertheless, superoxide dismutation (either spontaneously or enzimatically) leads to the synthesis of hydrogen peroxide, the more stable molecule of the ROS family [19]. In other words, NOXs maintain enzymatically intracellular levels of hydrogen peroxide, and together with mitochondria, sustain the oxidative power of the cell [7]. The NOX family is formed by 7 members, named NOX 1–5 and Duox 1–2. All these enzymes

Role of the NOX-derived hydrogen peroxide in neurogenesis and neural stem cell maintenance

Brain development is an extremely complex process in which several signaling pathways are involved. In mice, cerebral cortex development is initiated by the onset of neurogenesis that occurs at days 11–13 of embryonic development, in which neural stem cells (NSCs), the multipotent stem cells of the developing central nervous system, simultaneously experience asymmetric divisions, migration from the subventricular zone to the apical cortex through the radial glia, and neural polarization, the

The good and evil faces of ROS in neuronal functions: a matter of concentration

For many years, the concept of “oxidative stress” (recently re-called “distress” in Sies, to reinforce the negative consequence of an imbalanced hydrogen peroxide synthesis [12]) has been used to highlight the presence and role of pro-oxidative molecules in biological systems. However, the mere detection of these molecules does not necessarily represent a stressful condition. In the above sections, we summarized several important physiological roles that hydrogen peroxide play in nerve cells,

Final conclusions

This article summarizes the physiological and pathological contribution of ROS to neuronal development, including neurogenesis, polarization and maturation of neurons. It is important to make a clear difference between a stressful condition, where redox balance is lost and cellular homeostasis is compromised (here referred to as “oxidative distress”) and “oxidative eustress”, which refers to an adaptive response in conditions of physiological levels of hydrogen peroxide (the most stable and

Acknowledgments

This work was supported by CONICYT grants to CG-B under the Fondecyt (#1140325) and FONDAP (#15150012) programs. CW holds a postdoctoral fellowship from Consejo Nacional de Ciencia y Técnica (CONICET, Argentina). We thank Michael Handford for language support.

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