p38 MAPK: A dual role in hepatocyte proliferation through reactive oxygen species

Abstract

p38 MAPKs are important mediators of signal transduction that respond to a wide range of extracellular stressors such as UV radiation, osmotic shock, hypoxia, pro-inflammatory cytokines, and oxidative stress. The most abundant family member is p38α, which helps to couple cell proliferation and growth in response to certain damaging stimuli. In fact, increased proliferation and impaired differentiation are hallmarks of p38α-deficient cells. It has been reported that reactive oxygen species (ROS) play a critical role in cytokine-induced p38α activation. Under physiological conditions, p38α can function as a mediator of ROS signaling and either activate or suppress cell cycle progression depending on the activation stimulus. The interplay between cell proliferation, p38 MAPK activation, and ROS production plays an important role in hepatocytes. In fact, low levels of ROS seem to be needed to activate several signaling pathways in response to hepatectomy and to orchestrate liver regeneration. p38 MAPK works as a sensor of oxidative stress and cells that have developed mechanisms to uncouple p38 MAPK activation from oxidative stress are more likely to become tumorigenic. So far, p38α influences the redox balance, determining cell survival, terminal differentiation, proliferation, and senescence. Further studies would be necessary in order to clarify the precise role of p38 MAPK signaling as a redox therapeutical target.     

Peroxisomes sense and respond to environmental cues by regulating ROS and RNS signalling networks

Background Peroxisomes are highly dynamic, metabolically active organelles that used to be regarded as a sink for H₂O₂ generated in different organelles. However, peroxisomes are now considered to have a more complex function, containing different metabolic pathways, and they are an important source of reactive oxygen species (ROS), nitric oxide (NO) and reactive nitrogen species (RNS). Over-accumulation of ROS and RNS can give rise oxidative and nitrosative stress, but when produced at low concentrations they can act as signalling molecules.Scope This review focuses on the production of ROS and RNS in peroxisomes and their regulation by antioxidants. ROS production is associated with metabolic pathways such as photorespiration and fatty acid β-oxidation, and disturbances in any of these processes can be perceived by the cell as an alarm that triggers defence responses. Genetic and pharmacological studies have shown that photorespiratory H₂O₂ can affect nuclear gene expression, regulating the response to pathogen infection and light intensity. Proteomic studies have shown that peroxisomal proteins are targets for oxidative modification, S-nitrosylation and nitration and have highlighted the importance of these modifications in regulating peroxisomal metabolism and signalling networks. The morphology, size, number and speed of movement of peroxisomes can also change in response to oxidative stress, meaning that an ROS/redox receptor is required. Information available on the production and detection of NO/RNS in peroxisomes is more limited. Peroxisomal homeostasis is critical for maintaining the cellular redox balance and is regulated by ROS, peroxisomal proteases and autophagic processes.Conclusions Peroxisomes play a key role in many aspects of plant development and acclimation to stress conditions. These organelles can sense ROS/redox changes in the cell and thus trigger rapid and specific responses to environmental cues involving changes in peroxisomal dynamics as well as ROS- and NO-dependent signalling networks, although the mechanisms involved have not yet been established. Peroxisomes can therefore be regarded as a highly important decision-making platform in the cell, where ROS and RNS play a determining role.     

Current knowledge on oxidative stress in hepatic ischemia/reperfusion

Abstract

Ischemia/reperfusion (I/R) injury associated with hepatic resections and liver transplantation remains a serious complication in clinical practice, despite several attempts to solve the problem. The redox balance, which is pivotal for normal function and integrity of tissues, is dysregulated during I/R, leading to an accumulation of reactive oxygen species (ROS). Formation of ROS and oxidant stress are the disease mechanisms most commonly invoked in hepatic I/R injury. The present review examines published results regarding possible sources of ROS and their effects in the context of I/R injury. We also review the effect of oxidative stress on marginal livers, which are more vulnerable to I/R-induced oxidative stress. Strategies to improve the viability of marginal livers could reduce the risk of dysfunction after surgery and increase the number of organs suitable for transplantation. The review also considers the therapeutic strategies developed in recent years to reduce the oxidative stress induced by hepatic I/R, and we seek to explain why some of them have not been applied clinically. New antioxidant strategies that have yielded promising results for hepatic I/R injury are discussed.     

Generator-specific targets of mitochondrial reactive oxygen species

To understand the role of reactive oxygen species (ROS) in oxidative stress and redox signaling it is necessary to link their site of generation to the oxidative modification of specific targets. Here we have studied the selective modification of protein thiols by mitochondrial ROS that have been implicated as deleterious agents in a number of degenerative diseases and in the process of biological aging, but also as important players in cellular signal transduction. We hypothesized that this bipartite role might be based on different generator sites for “signaling” and “damaging” ROS and a directed release into different mitochondrial compartments. Because two main mitochondrial ROS generators, complex I (NADH:ubiquinone oxidoreductase) and complex III (ubiquinol:cytochrome c oxidoreductase; cytochrome bc₁ complex), are known to predominantly release superoxide and the derived hydrogen peroxide (H₂O₂) into the mitochondrial matrix and the intermembrane space, respectively, we investigated whether these ROS generators selectively oxidize specific protein thiols. We used redox fluorescence difference gel electrophoresis analysis to identify redox-sensitive targets in the mitochondrial proteome of intact rat heart mitochondria. We observed that the modified target proteins were distinctly different when complex I or complex III was employed as the source of ROS. These proteins are potential targets involved in mitochondrial redox signaling and may serve as biomarkers to study the generator-dependent dual role of mitochondrial ROS in redox signaling and oxidative stress.     

ROS and pentose phosphate pathway: mathematical modelling of the metabolic regulation in response to xenobiotic-induced oxidative stress and the proposed Impact of the gluconate shunt

Abstract

Elevated intracellular levels of reactive oxygen species (ROS), e.g. resulting from exposure to xenobiotics, can cause severe damages. Antioxidant defence mechanisms, which involve regulation of enzyme activities, protect cells to a certain extent. Nevertheless, continuous or increased exposure can overwhelm this system resulting in an adverse cellular state. To simulate exposure scenarios and to investigate the transition to an adverse cellular state, a mathematical model for the dynamics of ROS in response to xenobiotic-induced oxidative stress has been developed. It is based on exposure experiments of human urothelial cells (RT4) to the nitrated polycyclic aromatic hydrocarbon 3-nitrobenzanthrone (3-NBA), a component of diesel engine exhaust, and takes into account the following metabolic pathways of the antioxidant defence system: glutathione redox cycle scavenging directly ROS, the pentose phosphate pathway and the gluconate shunt as NADPH supplier and the beginning of glycolysis. In addition, ROS generation due to the bioactivation of 3-NBA has been implemented. The regulation of enzyme activities plays an important role in the presented mathematical model. The in silico model consists of ordinary differential equations on the basis of enzyme kinetics and mass action for the metabolism of 3-NBA. Parameters are either estimated from performed in vitro experiments via least-squares fitting or obtained from the literature. The results underline the importance of the pentose phosphate pathway to cope with oxidative stress and suggest an important role of the gluconate shunt during low-dose exposure.     

Redox regulation of SUMO enzymes is required for ATM activity and survival in oxidative stress

To sense and defend against oxidative stress, cells depend on signal transduction cascades involving redox‐sensitive proteins. We previously identified SUMO (small ubiquitin‐related modifier) enzymes as downstream effectors of reactive oxygen species (ROS). Hydrogen peroxide transiently inactivates SUMO E1 and E2 enzymes by inducing a disulfide bond between their catalytic cysteines. How important their oxidation is in light of many other redox‐regulated proteins has however been unclear. To selectively disrupt this redox switch, we identified a catalytically fully active SUMO E2 enzyme variant (Ubc9 D100A) with strongly reduced propensity to maintain a disulfide with the E1 enzyme in vitro and in cells. Replacement of Ubc9 by this variant impairs cell survival both under acute and mild chronic oxidative stresses. Intriguingly, Ubc9 D100A cells fail to maintain activity of the ATM–Chk2 DNA damage response pathway that is induced by hydrogen peroxide. In line with this, these cells are also more sensitive to the ROS‐producing chemotherapeutic drugs etoposide/Vp16 and Ara‐C. These findings reveal that SUMO E1~E2 oxidation is an essential redox switch in oxidative stress.     

An imbalance in antioxidant defense affects cellular function: the pathophysiological consequences of a reduction in antioxidant defense in the glutathione peroxidase-1 (Gpx1) knockout mouse

Abstract

Aerobic cells are subjected to damaging reactive oxygen species (ROS) as a consequence of oxidative metabolism and/or exposure to environmental toxins. Antioxidants limit this damage, yet peroxidative events occur when oxidant stress increases. This arises due to increased radical formation or decreased antioxidative defenses. The two-step enzymatic antioxidant pathway limits damage to important biomolecules by neutralising superoxides to water. However, an imbalance in this pathway (increased first-step antioxidants relative to second-step antioxidants) has been proposed as etiological in numerous pathologies. This review presents evidence that a shift in favor of hydrogen peroxide and/or lipid peroxides has pathophysiological consequences. The involvement of antioxidant genes in the regulation of redox status, and ultimately cellular homeostasis, is explored in murine transgenic and knockout models. The investigations of Sod1 transgenic cell-lines and mice, as well as Gpx1 knockout mice (both models favor H₂O₂ accumulation), are presented. Although in most instances accumulation of H₂O₂ affects cellular function and leads to exacerbated pathology, this is not always the case. This review highlights those instances where, for example, increased Sod1 levels are beneficial, and indicates a role for superoxide radicals in pathogenesis. Studies of Gpx1 knockout mice (an important second-step antioxidant) lead us to conclude that Gpx1 functions as the primary protection against acute oxidative stress, particularly in neuropathological situations such as stroke and cold-induced head trauma, where high levels of ROS occur during reperfusion or in response to injury. In summary, these studies clearly highlight the importance of limiting ROS-induced cellular damage by maintaining a balanced enzymatic antioxidant pathway.     

Inhibition of HAdV-14 induced apoptosis by selenocystine through ROS-mediated PARP and p53 signaling pathways

BackgroundHuman Adenovirus (HAdV) can cause severe respiratory symptoms in people with low immunity and there is no targeted treatment for adenovirus infection. Anti-adenoviral drugs have high clinical significance for inhibiting adenovirus infection. Selenium (Se) plays an important role in anti-oxidation, redox signal transduction, and redox homeostasis. The excellent biological activity of Se is mainly achieved by being converted into selenocystine (SeC). Se participates in the active sites of various selenoproteins in the form of SeC. The ability of SeC to resist the virus has raised high awareness due to its unique antioxidative activity in recent years. The antiviral ability of the SeC was determined by detecting the infection rate of the virus in the cells.MethodsThe experiment mainly investigated the antiviral mechanism of SeC by locating the virus in the cell, detecting the generation of ROS, observing the DNA status of the cell, and monitoring the mitochondrial membrane potential.ResultsIn the present study, SeC was designed to resist A549 cells infections caused by HAdV-14. SeC could prevent HAdV-14 from causing cell apoptosis-related to DNA damage. SeC significantly inhibited ROS generation and protect the cells from oxidative damage induced by ROS against HAdV-14. SeC induced the increase of antiviral cytokines such as IL-6 and IL-8 by activating the Jak2 signaling pathway, and repaired DNA lesions by suppressing ATR, p53, and PARP signaling pathways.ConclusionSeC might provide an effective selenium species with antiviral properties for the therapies against HAdV-14.     

A high-caloric diet rich in soy oil alleviates oxidative damage of skeletal muscles induced by dexamethasone in chickens

Objective: Glucocorticoids (GCs) can induce oxidative damage in skeletal muscles. The purpose of this study was to demonstrate a high caloric (HC) diet rich in soy oil would change the oxidative stress induced by a GC.

Methods: The effect of dexamethasone (DEX) and HC diet on oxidative stress in plasma, skeletal muscles (M. pectoralis major, PM; M. biceps femoris, BF), and mitochondria were determined. The biomarkers of oxidative damage and antioxidative enzyme activity were determined. The fatty acid profile of muscles and the activities of complex I and II in mitochondria were measured.

Results: The results showed that DEX increased the concentrations of oxidative damage markers in plasma, muscles, and mitochondria. The activity of complex I was significantly suppressed by DEX. DEX-chickens had higher proportions of polyunsaturated fatty acids and lower proportions of monounsaturated fatty acids in the PM. A HC diet decreased the levels of oxidative damage biomarkers in plasma, muscles, and mitochondria. The interaction between DEX and diet suppressed the activities of complex I and II in HC-chickens.

Discussion: Oxidative damage in skeletal muscles and mitochondria was the result of GC-induced suppression of the activity of mitochondrial complex I. A HC diet improved the antioxidative capacity and reduced the oxidative damage induced by the GC.     

Reactive oxygen species in vascular biology: implications in hypertension

Reactive oxygen species (ROS), including superoxide (·O₂^–), hydrogen peroxide (H₂O₂), and hydroxyl anion (OH-), and reactive nitrogen species, such as nitric oxide (NO) and peroxynitrite (ONOO^–), are biologically important O₂ derivatives that are increasingly recognized to be important in vascular biology through their oxidation/reduction (redox) potential. All vascular cell types (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) produce ROS, primarily via cell membrane-associated NAD(P)H oxidase. Reactive oxygen species regulate vascular function by modulating cell growth, apoptosis/anoikis, migration, inflammation, secretion, and extracellular matrix protein production. An imbalance in redox state where pro-oxidants overwhelm anti-oxidant capacity results in oxidative stress. Oxidative stress and associated oxidative damage are mediators of vascular injury and inflammation in many cardiovascular diseases, including hypertension, hyperlipidemia, and diabetes. Increased generation of ROS has been demonstrated in experimental and human hypertension. Anti-oxidants and agents that interrupt NAD(P)H oxidase-driven ·O₂^– production regress vascular remodeling, improve endothelial function, reduce inflammation, and decrease blood pressure in hypertensive models. This experimental evidence has evoked considerable interest because of the possibilities that therapies targeted against reactive oxygen intermediates, by decreasing generation of ROS and/or by increasing availability of antioxidants, may be useful in minimizing vascular injury and hypertensive end organ damage. The present chapter focuses on the importance of ROS in vascular biology and discusses the role of oxidative stress in vascular damage in hypertension.     

IDH2 deficiency promotes mitochondrial dysfunction and cardiac hypertrophy in mice

Cardiac hypertrophy, a risk factor for heart failure, is associated with enhanced oxidative stress in the mitochondria, resulting from high levels of reactive oxygen species (ROS). The balance between ROS generation and ROS detoxification dictates ROS levels. As such, disruption of these processes results in either increased or decreased levels of ROS. In previous publications, we have demonstrated that one of the primary functions of mitochondrial NADP⁺-dependent isocitrate dehydrogenase (IDH2) is to control the mitochondrial redox balance, and thereby mediate the cellular defense against oxidative damage, via the production of NADPH. To explore the association between IDH2 expression and cardiac function, we measured myocardial hypertrophy, apoptosis, and contractile dysfunction in IDH2 knockout (idh2^−/−) and wild-type (idh2^+/+) mice. As expected, mitochondria from the hearts of knockout mice lacked IDH2 activity and the hearts of IDH2-deficient mice developed accelerated heart failure, increased levels of apoptosis and hypertrophy, and exhibited mitochondrial dysfunction, which was associated with a loss of redox homeostasis. Our results suggest that IDH2 plays an important role in maintaining both baseline mitochondrial function and cardiac contractile function following pressure-overload hypertrophy, by preventing oxidative stress.     

Role of exercise-induced reactive oxygen species in the modulation of heat shock protein response

Abstract

The multiple roles that have been associated with heat shock proteins (HSPs), inside and outside cells are remarkable. HSPs have been found to play a fundamental role in multiple stress conditions and to offer protection from subsequent insults. Exercise, because of the physiological stresses associated with it, is one of the main stimuli associated with a robust increase of different HSPs in several tissues. Given the combination of physiological stresses induced by exercise, and the ‘cross-talk’ that occurs between signaling pathways in different tissues, it is likely that exercise induces the HSP expression through a combination of ‘stressors’, among which reactive oxygen species (ROS) could play a major role. Indeed, although an imbalance between ROS production and antioxidant levels results in oxidative stress, causing damage to lipids, proteins, and nucleic acids with a possible activation of the programed cell death pathway, at moderate concentrations ROS play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and re-establish redox homeostasis. The aim of this review is to provide a critical update on the role of exercise-induced ROS in the modulation of the HSP's response, focusing on experimental results from animal and human studies where the link between redox homeostasis and HSPs’ expression in different tissues has been addressed.     

多巴胺能神经元线粒体的氧化损伤与帕金森病

帕金森病(Parkinson’s disease,PD)的一个主要病理特征就是中脑黑质多巴胺能神经元的丧失,目前研究认为该病理变化与多种因素有关,包括蛋白质异常积聚、泛素蛋白酶体系统功能异常、神经炎症、线粒体损伤和氧化应激。在帕金森病人和动物模型中,中脑黑质有着明显的氧化改变。帕金森病的遗传和环境因素均会作用于线粒体,尤其对线粒体呼吸链复合体I有着抑制作用,造成线粒体损伤,产生活性氧(ROS)。活性氧的大量产生造成脂类、蛋白质和DNA的氧化,从而加剧多巴胺能神经元的线粒体和细胞损伤。多巴胺代谢过程中会产生活性氧,该自身代谢特点决定了多巴胺能神经元存在有较高的氧化应激,易受环境因素的影响。因而,线粒体的氧化损伤在帕金森病病理发生中起着重要作用。     

Reactive aldehydes – second messengers of free radicals in diabetes mellitus

Abstract

Elevated levels of pro-oxidants and various markers of oxidative tissue damage were found in diabetic patients, indicating involvement of oxidative stress in the pathogenesis of diabetes mellitus (DM). On one side, physiological levels of reactive oxygen species (ROS) play an important role in redox signaling of various cells, while on the other, excessive ROS production can jeopardize the integrity and physiological functions of cellular macromolecules, in particular proteins, thus contributing to the pathogenesis of DM. Reactive aldehydes, especially 4-hydroxynonenal (HNE), are considered as second messengers of free radicals that act both as signaling molecules and as cytotoxic products of lipid peroxidation causing long-lasting biological consequences, in particular by covalent modification of macromolecules. Accordingly, the HNE and related reactive aldehydes may play important roles in the pathophysiology of DM, both in the development of the disease and in its progression and complications due to the following: (i) exposure of cells to supraphysiological levels of 4-hydroxyalkenals, (ii) persistent and sustained generation of 4-hydroxyalkenals that progressively affect vulnerable cells that lack an efficient bioactive aldehyde neutralization system, (iii) altered redox signaling influenced by reactive aldehydes, in particular by HNE, and (iv) induction of extracellular generation of similar aldehydes under secondary pathological conditions, such as low-grade inflammation.     

Glutathione – linking cell proliferation to oxidative stress

SignificanceThe multifaceted functions of reduced glutathione (gamma-glutamyl–cysteinyl–glycine; GSH) continue to fascinate plants and animal scientists, not least because of the dynamic relationships between GSH and reactive oxygen species (ROS) that underpin reduction/oxidation (redox) regulation and signalling. Here we consider the respective roles of ROS and GSH in the regulation of plant growth, with a particular focus on regulation of the plant cell cycle. Glutathione is discussed not only as a crucial low molecular weight redox buffer that shields nuclear processes against oxidative challenge but also a flexible regulator of genetic and epigenetic functions.Recent advancesThe intracellular compartmentalization of GSH during the cell cycle is remarkably consistent in plants and animals. Moreover, measurements of in vivo glutathione redox potentials reveal that the cellular environment is much more reducing than predicted from GSH/GSSG ratios measured in tissue extracts. The redox potential of the cytosol and nuclei of non-dividing plant cells is about −300 mV. This relatively low redox potential maintained even in cells experiencing oxidative stress by a number of mechanisms including vacuolar sequestration of GSSG. We propose that regulated ROS production linked to glutathione-mediated signalling events are the hallmark of viable cells within a changing and challenging environment.Critical issuesThe concept that the cell cycle in animals is subject to redox controls is well established but little is known about how ROS and GSH regulate this process in plants. However, it is increasingly likely that redox controls exist in plants, although possibly through different pathways. Moreover, redox-regulated proteins that function in cell cycle checkpoints remain to be identified in plants. While GSH-responsive genes have now been identified, the mechanisms that mediate and regulate protein glutathionylation in plants remain poorly defined.Future directionsThe nuclear GSH pool provides an appropriate redox environment for essential nuclear functions. Future work will focus on how this essential thiol interacts with the nuclear thioredoxin system and nitric oxide to regulate genetic and epigenetic mechanisms. The characterization of redox-regulated cell cycle proteins in plants, and the elucidation of mechanisms that facilitate GSH accumulation in the nucleus are keep steps to unravelling the complexities of nuclear redox controls.     

The cellular redox state as a modulator in cadmium and copper responses in Arabidopsis thaliana seedlings

The cellular redox state is an important determinant of metal phytotoxicity. In this study we investigated the influence of cadmium (Cd) and copper (Cu) stress on the cellular redox balance in relation to oxidative signalling and damage in Arabidopsis thaliana. Both metals were easily taken up by the roots, but the translocation to the aboveground parts was restricted to Cd stress. In the roots, Cu directly induced an oxidative burst, whereas enzymatic ROS (reactive oxygen species) production via NADPH oxidases seems important in oxidative stress caused by Cd. Furthermore, in the roots, the glutathione metabolism plays a crucial role in controlling the gene regulation of the antioxidative defence mechanism under Cd stress. Metal-specific alterations were also noticed with regard to the microRNA regulation of CuZnSOD gene expression in both roots and leaves. The appearance of lipid peroxidation is dual: it can be an indication of oxidative damage as well as an indication of oxidative signalling as lipoxygenases are induced after metal exposure and are initial enzymes in oxylipin biosynthesis.In conclusion, the metal-induced cellular redox imbalance is strongly dependent on the chemical properties of the metal and the plant organ considered. The stress intensity determines its involvement in downstream responses in relation to oxidative damage or signalling.     

RASSF1A suppresses the activated K-Ras-induced oxidative DNA damage

The mutant K-Ras elevates intracellular reactive oxygen species (ROS) levels and leads to oxidative DNA damage, resulting in malignant cell transformation. Ras association domain family 1 isoform A (RASSF1A) is known to play a role as a Ras effector. However, the suppressive effect of RASSF1A on K-RasV12-induced ROS increase and DNA damage has not been identified. Here, we show that RASSF1A blocks K-RasV12-triggered ROS production. RASSF1A expression also inhibits oxidative DNA damage and chromosomal damage. From the results obtained in this study, we suggest that RASSF1A regulates the cellular ROS levels enhanced by the Ras signaling pathway, and that it may function as a tumor suppressor by suppressing DNA damage caused by activated Ras.     

SIRT5 promotes IDH2 desuccinylation and G6PD deglutarylation to enhance cellular antioxidant defense

Excess in mitochondrial reactive oxygen species (ROS) is considered as a major cause of cellular oxidative stress. NADPH, the main intracellular reductant, has a key role in keeping glutathione in its reduced form GSH, which scavenges ROS and thus protects the cell from oxidative damage. Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose‐6‐phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH‐producing enzymes. Moreover, we show that knockdown or knockout of SIRT5 leads to high levels of cellular ROS. SIRT5 inactivation leads to the inhibition of IDH2 and G6PD, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress. Our study uncovers a SIRT5‐dependent mechanism that regulates cellular NADPH homeostasis and redox potential by promoting IDH2 desuccinylation and G6PD deglutarylation.     

Oxidative stress tolerance in plants: Novel interplay between auxin and reactive oxygen species signaling

Biotic and abiotic stress conditions produce reactive oxygen species (ROS) in plants causing oxidative stress damage. At the same time, ROS have additional signaling roles in plant adaptation to the stress. It is not known how the two seemingly contrasting functional roles of ROS between oxidative damage to the cell and signaling for stress protection are balanced. Research suggests that the plant growth regulator auxin may be the connecting link regulating the level of ROS and directing its role in oxidative damage or signaling in plants under stress. The objective of this review is to highlight some of the recent research on how auxin’s role is intertwined to that of ROS, more specifically H₂O₂, in plant adaptation to oxidative stress conditions.     

The MnSOD Ala16Val SNP: Relevance to human diseases and interaction with environmental factors

Abstract

The relevance of reactive oxygen species (ROS) production relies on the dual role shown by these molecules in aerobes. ROS are known to modulate several physiological phenomena, such as immune response and cell growth and differentiation; on the other hand, uncontrolled ROS production may cause important tissue and cell damage, such as deoxyribonucleic acid oxidation, lipid peroxidation, and protein carbonylation. The manganese superoxide dismutase (MnSOD) antioxidant enzyme affords the major defense against ROS within the mitochondria, which is considered the main ROS production locus in aerobes. Structural and/or functional single nucleotide polymorphisms (SNP) within the MnSOD encoding gene may be relevant for ROS detoxification. Specifically, the MnSOD Ala16Val SNP has been shown to alter the enzyme localization and mitochondrial transportation, affecting the redox status balance. Oxidative stress may contribute to the development of type 2 diabetes, cardiovascular diseases, various inflammatory conditions, or cancer. The Ala16Val MnSOD SNP has been associated with these and other chronic diseases; however, inconsistent findings between studies have made difficult drawing definitive conclusions. Environmental factors, such as dietary antioxidant intake and exercise have been shown to affect ROS metabolism through antioxidant enzyme regulation and may contribute to explain inconsistencies in the literature. Nevertheless, whether environmental factors may be associated to the Ala16Val genotypes in human diseases still needs to be clarified.