Manganese Superoxide Dismutase and Oxidative Stress Modulation Guilherme Bresciani*,1, Ivana Beatrice M^anica da Cruz†, Javier González-Gallego{ *Facultad de Ciencias de la Salud, Universidad Auto´noma de Chile, Temuco, Chile † Laborato´rio de Biogenoˆmica, Departamento de Morfologia, Universidade Federal de Santa Maria, Santa Maria, Brazil { Institute of Biomedicine (IBIOMED) and Centro de Investigacio´n Biome´dica en Red de Enfermedades Hepa´ticas y Digestivas (CIBERehd), University of Leo´n, Leo´n, Spain 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Oxidative Stress: A Brief Review 2.1 Mitochondrial role in energy production 2.2 ROS generation and effects in the organism 3. Superoxide Dismutase in Antioxidant Defense 3.1 Antioxidant defense 3.2 Superoxide dismutase 4. MnSOD and Oxidative Stress Modulation 4.1 Nervous system 4.2 Metabolic-related conditions 4.3 Cardiovascular system 5. Environmental Factors, Genetics, and MnSOD Modulation 5.1 Exercise, oxidative stress, and health: Evidence for MnSOD involvement 6. Conclusions Acknowledgments References

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Abstract Oxidative stress is characterized by imbalanced reactive oxygen species (ROS) production and antioxidant defenses. Two main antioxidant systems exist. The nonenzymatic system relies on molecules to directly quench ROS and the enzymatic system is composed of specific enzymes that detoxify ROS. Among the latter, the superoxide dismutase (SOD) family is important in oxidative stress modulation. Of these, manganese-dependent SOD (MnSOD) plays a major role due to its mitochondrial location, i.e., the main site of superoxide (O2 • ) production. As such, extensive research has

Advances in Clinical Chemistry ISSN 0065-2423


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focused on its capacity to modulate oxidative stress. Early data demonstrated the relevance of MnSOD as an O2 • scavenger. More recent research has, however, identified a prominent role for MnSOD in carcinogenesis. In addition, SOD downregulation appears associated with health risk in heart and brain. A single nucleotide polymorphism which alters the mitochondria signaling sequence for the cytosolic MnSOD form has been identified. Transport into the mitochondria was differentially affected by allelic presence and a new chapter in MnSOD research thus begun. As a result, an everincreasing number of diseases appear associated with this allelic variation including metabolic and cardiovascular disease. Although diet and exercise upregulate MnSOD, the relationship between environmental and genetic factors remains unclear.

ABBREVIATIONS AD Alzheimer’s disease AIF apoptosis-inducing factor Ala alanine ATP adenosine triphosphate BD bipolar I disorder CADs cardiovascular diseases CAT catalase CNS central nervous system Cu/ZnSOD cytosolic copper–zinc-dependent superoxide dismutase Cyt c cytochrome c DNA deoxyribonucleic acid ETC electron transport chain ecSOD extracellular superoxide dismutase FEP first episode psychosis GPx glutathione peroxidase GSH glutathione HCC hepatocellular carcinoma HCV hepatitis C virus HHC hereditary hemochromatosis HDL high-density lipoprotein LDL low-density lipoprotein MDA malondialdehyde MDD major depressive disorder MnSOD manganese-dependent superoxide dismutase mRNA messenger ribonucleic acid mtDNA mitochondrial deoxyribonucleic acid ox-LDL oxidized low-density lipoprotein PD Parkinson’s disease rDD recurrent depressive disorder RNA ribonucleic acid ROS reactive oxygen species SNP single nucleotide polymorphism

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SOD superoxide dismutase TD tardive dyskinesia Val valine 8-OhdG 8-hydroxy-2’deoxyguanosine α alpha β beta

1. INTRODUCTION During the last few decades, researchers in biochemistry, biology, chemistry, and physiology have studied the self-regulating modulation of the bioenergetics of aerobes, i.e., “oxidative stress.” The growing interest in this phenomenon is due to the peculiar characteristics presented by oxidative stress that change the way we perceive this vital molecule, oxygen (O2). O2 is essential for aerobic survival in our oxygen-rich atmosphere has played a major role in aerobic evolution due to its unique properties as the final electron acceptor of the mitochondrial electron transport chain (ETC) [1]. Without O2, organisms would have been unable to evolve into more complex multicellular life forms. Bioenergetics would be decreased and less effective, thus directly affecting reproduction and dampening propagation of varieties and species. Nevertheless, O2 metabolism also presented aerobes with a challenge. It is well known that more than 90% of the body’s O2 is consumed by the ETC in mitochondria [2]. O2 reduction is, however, complex, i.e., the molecule has two parallel spinning unpaired electrons in its outermost orbital [3]. According to Pauli’s Exclusion Principle, it is impossible to reduce O2 in one step. Consequently, it undergoes a one-electron reduction to produce the first free radical found in aerobes, the superoxide anion (O2 • ) [4]. Intermediates in the O2 reduction process are called free radicals—molecules that contain an unpaired electron (radical) and are capable of independent existence (free) [3]. Free radicals derived from O2 metabolism are also known as reactive oxygen species (ROS) [5]. The relevance of the ROS relies on their dual role in aerobes (Fig. 1). At physiologic concentration, ROS have been implicated in modulation of gene expression and cellular signaling [6]. First recognized as toxic metabolites of O2 metabolism, ROS are now known to be significant modulators of different signaling pathways [7,8]. In addition, they play a key role in


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Figure 1 Reactive oxygen species (ROS)-mediated actions in the organism. The mitochondrial electron transport chain (ETC) ROS production is related to both physiological- and pathological-related mechanisms.

inflammation via adhesion and chemotaxic molecules. Uncontrolled ROS release, however, leads to oxidation of cellular components, such as proteins, lipids, and deoxyribonucleic acid (DNA). As such, uncontrolled ROS production by oxidative metabolism and other sources may cause distress leading to cellular damage [9]. Therefore, ROS are linked to physiologic and pathophysiologic conditions depending on the balance of production and clearance. Equilibrium between oxidants and antioxidants is required to reach homeostasis. Oxidative imbalance may result in pathologic response and lead to important functional disruptions and associated diseases. Over the last few decades, oxidative stress and its role in pathology have been extensively studied. A few ROS-related molecular pathways have been identified and subsequently linked to metabolic-related diseases. Harman was the first scientist to propose a link between free radicals and deleterious effects to the organism, stating that aging was a process that was at least in part caused by free radicals [10]. Among the most studied and well-described oxidative stress-related diseases are cardiovascular diseases (CADs) [11], metabolic-related [12], and neurodegenerative conditions [13]. Nevertheless, the exact role of oxidative stress as a disease cause or consequence has yet to be fully clarified. Epidemiologic and associative studies established a potential relationship between genetics and diseases in the early 1990s. Research has evaluated the effects of genes and single nucleotide polymorphisms (SNPs) on the expression of proteins’ key to oxidative stress control, i.e., antioxidant enzymes. Therefore, elucidation of the molecular biology and the genetics of key antioxidant proteins have achieved more prominence in recent years.

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2. OXIDATIVE STRESS: A BRIEF REVIEW The O2 molecule was introduced into earth’s atmosphere approximately 2–3 billion years ago due to the evolution of O2-releasing photosynthetic organisms. Current levels (21%) were reached within a few million years. This O2-loaded environment applied selective pressure to living organisms and ultimately led to propagation of aerobes. The great advantage provided by oxidative metabolism relied on complete combustion of glucose [14]. O2 oxidized biologic substrates to supply energy for aerobic survival [15] and played a key role as an electron acceptor in the ETC [16]. This process is not a single-step reaction, but an electron transfer sequence mediated through enzymatic systems that lead to the final electron acceptor. In 1954, Commoner and coworkers identified free radicals in biologic tissues [17]. Denham Harman then hypothesized that O2 radicals were produced as byproducts of enzyme activities in vivo [10]. Free radicals were described as a “Pandora’s box” due to their potential involvement in cell damage, mutagenesis, cancer, and the degenerative process of aging. As such, excessive ROS production likely triggers cellular/tissue damage the extent of which is related to cellular redox state. Cells are able to maintain a redox state when low or moderate levels of ROS are produced, whereas increased ROS overwhelm antioxidant defense leading to oxidative stress and cellular damage [18]. Redox state disruption may cause toxicity via production of peroxides and free radicals and some irreversible damage may occur. The mitochondrion is one of the main intracellular sites for ROS production [19,20]. From this point, cellular damage accumulates ultimately degrading the physiologic capacities of various systems, and leading to CADs [21,22], metabolic-related conditions [23,24], and neurodegenerative disorders [25,26].

2.1. Mitochondrial role in energy production Mitochondria are ubiquitous organelles that perform crucial cellular functions in eukaryotes and, as such, have been considered “gatekeepers of life and death” [27]. Major mitochondrial processes include the production of over 90% of cellular adenosine triphosphate (ATP), regulation of intracellular calcium (Ca2+), redox signaling, and modulation of apoptosis [28,29]. The majority of biochemical energy required for cell function is produced in the mitochondria. Energy generation occurs through ATP


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turnover during oxidative phosphorylation in the ETC with O2 as substrate. This metabolic reaction takes place in the mitochondrial inner membrane and is driven by the release of a proton gradient generated by the pumping of hydrogen (H+) into the intermembrane space by metabolic reactions via cytochromes. Electrons released through the metabolism of carbohydrate and fatty acid metabolism are captured by nicotine adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD) systems, that act as electron carriers in the ETC. Electron transport into the mitochondria generates an electrochemical gradient across the inner mitochondrial membrane. Decreased ATP concentration triggers proton transfer through ATP synthase into the mitochondrial matrix and this energy is captured to generate ATP [30]. During this process, however, 2–5% of O2 undergoes univalent reduction generating O2 • [31], the first ROS produced by this pathway [32]. As such, ROS are atoms or molecules with one unpaired electron in their outermost shell which renders them highly reactive and unstable [3,32]. This species reacts with other atoms or molecules via oxidation–reduction that, in turn, activate a cascade of ROS production. Thus, formation of O2 • during cell respiration can give rise to other ROS.

2.2. ROS generation and effects in the organism ROS can be produced by other processes including catecholamine autooxidation, immune system cell activation, ischemia, and/or hypoxia– reperfusion damage [31]. ROS can also be generated by estrogens and their metabolites, by a variety of xenobiotics and by the xanthine–xanthine oxidase system [15]. Despite these ancillary sources, mitochondrial O2 • mediated ROS represents the most relevant cascade of production (Fig. 2). Hydrogen peroxide (H2O2) is synthesized by bivalent reduction of O2 with the addition of two protons (H+). It is noteworthy that dismutation of O2 • can also produce H2O2[14]. Reaction of free iron (Fe2+) and H2O2 generates hydroxyl radical (OH•), which appears responsible for lipid, protein, and DNA damage [34]. OH• is very reactive and toxic, and there is no specific antioxidant enzyme against this ROS [35]. Hypochlorous acid is generated via action of myeloperoxidase on H2O2. Although this strong oxidant is important for destruction-ingested microorganisms, it can also harm neighboring tissues via oxidation of thiols, lipids, and ascorbate [34]. O2 • dismutation can also produce singlet oxygen (1O2),

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Figure 2 Reactive oxygen production (ROS) in the mitochondria and cytosol. NADH collects electrons from the oxygen molecules (O2). The electrons subsequently flow through the mitochondrial electron transport chain (ETC) complexes for ATP resynthesis. A small amount of the O2 undergoes an incomplete reduction giving rise to the superoxide anion (O2 • ), the first ROS within the aerobic organisms. After, the manganese-dependent superoxide dismutase (MnSOD) dismutates the O2 • into hydrogen peroxide (H2O2) and O2; the H2O2 is further neutralized by the glutathione peroxidase (GPx) into H2O with glutathione (GSH) as a substrate. Equally, H2O2 may be also converted into the hazardous hydroxyl radical (OH•) through Fenton reaction with iron (Fe2+). Outside the mitochondria, the O2 can also be converted into O2 • through an NADPH-oxidase reaction with nicotinamide adenine dinucleotide phosphate (NADPH) as substrate. Further, the copper–zinc-dependent superoxide dismutase (Cu/ZnSOD) dismutates the O2 • in the membrane interspace while the same reaction takes place in the extracellular milieu by the extracellular superoxide dismutase (ecSOD). Here, the H2O2 is also neutralized by the GPx, although catalase (CAT) also reacts with this ROS. The O2 molecule may also give rise to the nitric oxide (NO•) across a nitric oxide synthase (NO synthase) reaction using arginine as a substrate. The NO• may also react with the O2 • to form the highly reactive peroxynitrite anion (ONOO). Adapted from Ref. [33].


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which has no unpaired electrons but has strong oxidizing ability [34]. Peroxynitrite (ONOO), a reaction product of NO• and O2 • , is a potent and versatile oxidant that attacks a wide range of biologic molecules causing thiol depletion, DNA damage and protein nitration [36]. This process is widely believed to represent a major pathway for reactive nitrogen species (RNS) generation [14,37]. Therefore, ROS imbalance can also result in nitrosative stress, which has been implicated in a variety of disorders including neurovascular pathogenic cascades [38], CADs [39], and diabetes [40]. Although O2 • and NO• have relevant physiologic roles at low concentration, increased ROS is harmful [41–44]. Elucidation of ROS mechanisms of action will improve our understanding of the fundamental processes involved with disease biology and pathophysiology. 2.2.1 Lipid peroxidation Lipid peroxidation is a physiologic process primarily affecting cell membranes. Peroxidation of polyunsaturated fatty acids occurs as a consequence of double bond weakening, production of conjugated dienes, O2 addition, peroxy radical formation, and H+ loss from lipid. Because cells do not have mechanisms to dispose of these byproducts, lipid peroxidation is considered irreversible [45]. This phenomenon may lead to accumulated cell damage classified as (1) changes to membrane-associated enzymes, ionic channels or receptors that activate or inactivate them [46], (2) the opening of new channels of cell permeability [47], (3) the formation of cross-linked proteins (irreversible inactivation) [48], and (4) sulfhydryl group oxidation at the active sites of membrane-bound enzymes [49]. Additionally, based on the magnitude of ROS damage, losses in cell membrane fluidity and secretory functions may also be observed. Damage to specific organelles, i.e., lysosomes, may result in the release of phospholipases and other enzymes that promote additional membrane degradation [50]. Increased membrane permeability results in facilitated ion influx that activates phospholipases, thus promoting additional permeability [51]. 2.2.2 Protein and enzyme oxidation and glycosylation ROS interaction with enzymes and other proteins (structural, receptors, and transporters) can induce the oxidation of sulfhydryl groups, methionine, and amino acids [52]. Introduction of carbonyl groups affects both the structure and activity of these proteins [53]. Some of these groups are easily oxidized and the damage, similar to that in lipid, is irreversible. As such, protein carbonylation is considered an irreversible posttranslational modification [54].

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ROS may induce protein cross-linking, aggregation, and denaturation, causing a cascade of damage [55]. Protease inhibitors can also become inactive, inducing relevant physiologic alterations. Damage to channel proteins can lead to disrupted cell function due to ion imbalance [56]. 2.2.3 Metabolic disruption Mitochondrial ETC complexes I and III are the primary sites of ROS production and release [21,27]. Complex III produces O2 • by autooxidation of the ubisemiquinone radical intermediate (QH•). The Qo site is the major O2 • producer in the inner membrane. The complex III Qi site is closer to the matrix side and is less likely to react with oxygen and form O2 • , i.e., this site firmly binds QH• and stabilizes it in the matrix [21]. Complex III has the capacity to release O2 • to both sides of the mitochondrial inner membrane depending on which portion of the Q cycle is involved [57]. The precise mechanisms of complex I O2 • generation are largely unknown. However, it has been suggested that complex I produces O2 • by reverse electron transfer from complex II during succinate oxidation in the absence of NADH-linked substrates. Alternatively, much lower amounts may be generated by forward electron transfer from the NADH-linked substrates. Interestingly, the latter mechanism may account for more of the physiologically relevant ROS produced in the mitochondria [58,59]. The NADH coenzyme transports a large quantity of chemical energy in reduced form and O2 • electron capture interferes with the NADH oxidation to NAD+ thus affecting metabolic roles of NADH in antioxidant defense and ATP turnover [60]. Therefore, the effects of ROS on energy transport molecules greatly control energy production and use. 2.2.4 Oxidation of nuclear and mitochondrial nucleic acids When antioxidant defenses are overwhelmed, DNA can suffer direct ROSmediated damage through H2O2 and OH•. Nucleotide modification and DNA rupture are the major consequences of this damage [61], including single- and double-stranded breaks, DNA–DNA and DNA–protein cross-links, and base modifications [62]. Although repairable, multiple ROS-mediated lesions in proximal nucleotides (tandem lesions) overwhelm DNA repair mechanisms and induce deleterious genetic change over time [63]. ROS damage is also a challenge to mitochondrial DNA (mtDNA). The mitochondrion has its own DNA which codes for specific ribonucleic acids (RNAs) necessary for homeostasis. Studies have demonstrated that mtDNA


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is also susceptible to ROS-mediated damage [64–66]. In fact, mtDNA is more sensitive than nuclear DNA to ROS damage due to its lack of repair processes. As can be expected, accumulation of oxidative damage within mitochondria and mtDNA likely increases mutation rates, leading to decreased bioenergetic function and increased cell dysfunction [62,63].

3. SUPEROXIDE DISMUTASE IN ANTIOXIDANT DEFENSE 3.1. Antioxidant defense Organisms use nonenzymatic and enzymatic antioxidant systems to protect against ROS and subsequent damage to membranes and macromolecules. These important systems are responsible for homeostasis and genomic integrity. The nonenzymatic system is composed of a myriad of antioxidant molecules such as retinol, ascorbic acid, tocopherol, flavonoids, thiols, uric acid, ferritin, bilirubin, and a few micronutrients [67]. The antioxidant molecules directly quench ROS thus preventing oxidative damage [35]. Main antioxidant enzymes are superoxide dismutase (SOD, EC, superoxide:superoxide oxidoreductase), glutathione peroxidase (GPx, EC, glutathione:hydrogen peroxide oxidoreductase), and catalase (CAT, EC, hydrogen peroxide:hydrogen peroxide oxidoreductase) [68]. These enzymes are compartment specific and regulated genetically [69]. SOD dismutates O2 • into H2O2 to avoid accumulation to toxic level [70]. The primary mechanism to eliminate H2O2 and lipid peroxides in the cytosol and mitochondria is catalyzed by GPx, which uses glutathione (GSH) to reduce H2O2 and hydroperoxides into water and alcohols, respectively [71]. CAT is one of the most abundant peroxisomal proteins in mammalian cells and converts H2O2 into H2O and O2[72] (Fig. 2). GPx, located in the cytosol and mitochondria, detoxifies H2O2 and hydroperoxides (ROOH) into H2O and alcohols (ROH), respectively [35,71]. Different GPx isoforms have been identified in mammals [73]. Although sharing the ability to reduce H2O2, isoforms differ in tissue expression and substrate requirement [74]. This unique characteristic optimizes their antioxidant role [71]. CAT is a homotetramer with a molecular weight of 240 kDa [75]. Although its primary role is to catalyze the hydrolysis of H2O2 into H2O and O2, the enzyme has been implicated in several biochemical pathways. Despite its ubiquitous distribution, CAT is primarily localized in peroxisomes which use O2 • to detoxify organic byproducts [76] and produce H2O2. Although CAT performs the same catalytic reaction as

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GPx, it has higher affinity for H2O2[71]. As such, CAT may represent an important protective mechanism against increased H2O2 concentration due to its higher Km.

3.2. Superoxide dismutase SOD is the first line of defense in the antioxidant enzyme repertoire, catalyzing O2 • anion dismutation into O2 and H2O2. This remarkable discovery was first reported by McCord and Fridovich in the late 1960s. This finding suggested that the copper-based protein described by Mann and Keilin could catalyze Pauling free radical (O2 • ) reduction [69]. Its final product, H2O2, is less reactive and generation of highly reactive OH• radical is avoided. Three isoforms of SOD have been described in humans. These include the cytosolic copper–zinc-dependent form (CuZnSOD, SOD1), the mitochondrial manganese-dependent form (manganese-dependent SOD [MnSOD], SOD2), and the extracellular copper–zinc-dependent form (extracellular SOD [ecSOD], SOD3). It is noteworthy that each isoform requires a redox transition metal in its active site to dismutate O2 • . This finding may, in fact, partially explain the enormous relevance of dietary micronutrients [77]. SOD1 requires copper and zinc as cofactors and is located in the cytosol, nucleus, peroxisomes, and intermembrane space of the mitochondria [78]. This isoform is essential for antioxidant defense and mutations of this enzyme have been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis [79,80]. The ecSOD isoform also requires copper and zinc as cofactors for redox activity maintenance. The ecSOD isoform is produced by smooth muscle cells and released [81]. Due to its extracellular location, ecSOD has been hailed as the principal regulator of endothelium-derived NO• bioactivity through its O2 • scavenging activity [77,82]. ecSOD is present in blood vessels, heart, lungs, bladder, and extracellular fluids [78]. It has been suggested that ecSOD plays an important role in neurologic and cardiovascular disorders [78,81]. Unlike Cu/Zn-dependent SODs, mitochondrial SOD requires manganese as a cofactor. MnSOD, the only isoform present in mitochondria, is considered essential for aerobic survival [83,84]. Genetic studies have revealed that the null homozygous mutation (MnSOD/) is lethal, whereas knockouts of Cu/ZnSOD and GPx are not [85]. MnSOD-knockout mice have severe mitochondrial damage, decreased GSH, increased 8hydroxy-20 deoxyguanosine (8-OhdG), and diminished respiratory control


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[86,87]. These animals do not survive to adulthood and die shortly after birth. Heterozygous MnSOD-knockout mice with 50% enzyme activity also show increased 8-OhdG DNA damage in nuclear and mtDNA versus wild-type controls [88]. The short lifespan in MnSOD knockouts is likely related to the enzyme’s role in maintaining nanomolar or lower O2 • concentration [89]. Antioxidant activity of the aforementioned enzymes may be affected by several factors. Nature and nurture both play roles in antioxidant modulation in aerobes. Diet, alcohol consumption, and physical activity may induce relevant changes at the molecular level, especially in humans. Increased understanding of the role of the environment in the molecular biology of organisms will be discussed below. 3.2.1 MnSOD and the Ala16ValSNP The SNP is the most common genetic mutation and occurs at a frequency of 1% in humans [90]. SNP has important roles in biosciences and serves as genetic markers of different diseases [91] and is responsible for 90% of all human genetic variation [92]. The SNP is characterized by a single base change or deletion within a gene that can potentially lead to amino acid modification in specific proteins to influence phenotypic alteration [93]. While “silent” SNP is benign, others may alter protein structure and function [94]. It is estimated that an average of one SNP occurs for every 1000–2000 nucleotide bases; depending on the DNA region, this ratio may reach one in 300 [91,95]. As can be expected, variation in DNA sequence may lead to altered immune mechanisms in response to disease, bacteria, virus, and xenobiotic exposure [91]. In fact, SNPs have been described for the most genes encoding the main antioxidant enzymes. The SNP in the GPx1 gene (Pro198Leu, rs1050450) has been identified in erythrocytes and several epithelial tissues including breast [96]. The CAT C262T (rs1001179) SNP alters the transcription factor binding and basal CAT activity in red blood cells [97]. More than 190 SNPs have been detected for MnSOD, which may explain its relevance as a first line of antioxidant defense to ROS [93,98]. The main SNPs described so far for the MnSOD are Ile58Thr (rs1141718) and Ala16Val (rs4880) for MnSOD. Substitution of isoleucine (Ile) for threonine (Thr) at amino acid position 58 has been linked to tumor suppression in human breast cancer cells [99]. The most studied SNP, Ala16Val, results from the substitution of cytosine for thymine in exon 2. At the protein level, this genetic change results in substitution of valine (Val) for alanine (Ala) in codon 16 [100]. The single

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Figure 3 Manganese-dependent superoxide dismutase (MnSOD) content in the mitochondria according to different Ala16Val precursors. While the alanine (Ala) precursor is correctly transported across both mitochondrial membranes (MTS-Ala), the valine (Val) precursor is partially arrested in the inner membrane (MTS-Val). The increased MnSOD content afforded by the Ala precursor is translated into a more efficient superoxide (O2 • ) detoxification, whereas the Val precursor leads to O2 • accumulation in the mitochondria. Adapted from Ref. [101].

amino acid substitution results in a distinct conformational change (β [beta]sheet to α [alpha]-helix) in this region which modifies the mitochondrial import of MTS-MnSOD. While the majority of the Val variant is embedded within the mitochondrial inner membrane, the Ala variant easily crosses both mitochondrial membranes to reach the matrix (Fig. 3) [102]. Previous studies have found a more active (30–40%), matrix-localized and processed MnSOD homotetramer for the Ala–MnSOD precursor [103].

4. MnSOD AND OXIDATIVE STRESS MODULATION Consistent with its role in ROS detoxification via O2 • dismutation, MnSOD is important in a number of physiologic systems. MnSOD upregulation was shown to mitigate apoptosis in brain [104], diabetic cardiopathy [105], cell signaling death in liver [106], and restored redox balance in the skeletal muscle following exercise [107]. ROS are frequently associated with pathophysiology and an increasing number of diseases are associated with ROS activity as an etiologic agent or contributing factor [108]. Several studies have shown that MnSOD induction can protect against


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neurotoxic conditions [102], cardiomyopathy [105,109], and diabetic disorders [110,111]. Environmental and/or genetic factors that modulate antioxidant response to different stimuli have been described. The relationship between the mutation of genes encoding antioxidant enzymes and oxidative stress-related diseases has generated growing interest in how these SNPs might be useful in understanding disease-related pathways [101]. An increasing number of studies have investigated the relationship of the Ala16Val SNP with neural, metabolic, and CAD.

4.1. Nervous system Although the brain represents only 2% human body weight, 15% of cardiac output, and 20% of total body O2 consumption are driven by this organ [112,113]. This increased metabolism is largely due to neuronal energy demand for maintaining ion gradients across the plasma membrane which is critical to action potentials [112]. As such, the brain is especially prone to ROS-mediated damage due to increased O2 consumption, polyunsaturated fatty acids and transition metals, and reduced antioxidant defenses [25]. The balance between O2 • and H2O2 production/catalysis represents a crucial component of cell metabolism. In addition, these molecules are highly relevant to signaling pathways that respond to a wide range of physiologic conditions. O2 • and H2O2 production/catalysis is particularly important to the central nervous system (CNS) and peripheral nervous system (PNS), given cyto-anatomic and functional nature of neuronal cells. In general, neurons are highly complex cells with extremely long processes, i.e., axons may extend up to 1 m in motor neurons. This structure is important to guarantee the major neural function of communication with other body cells and tissues [114]. Neuronal architecture requires highly organized organellar transport, especially for mitochondria, which produces metabolic energy. Regulation of mitochondrial activity is particularly important in brain, an organ highly dependent on oxidative phosphorylation for ATP. High ATP demand results in significant ROS production primarily controlled by antioxidant enzymes thus avoiding oxidative stress. Neuronal oxidative stress has been linked to apoptosis and implicated in neurodegenerative diseases [26]. SOD imbalance appears related to several neurodegenerative conditions due to O2 • -mediated damage to ETC components and other cellular constituents [115]. Excessive ROS, generated from mitochondrial dysfunction, accumulation of transition metals or β-amyloid peptide and tau proteins

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(proteins that stabilize microtubules), promote redox imbalance [116]. Despite the apparent role of oxidative stress in Alzheimer’s disease (AD), clinical management failed to demonstrate clear benefit of antioxidant therapy [117]. Significant heterogeneity in research design, differential control of confounders, insufficient measures of cognitive performance, and difficulty with dietary assessment likely contributed to poor study outcome [118]. Despite these findings, imbalance associated with antioxidant enzyme deregulation may be core to AD initiation and progression. This hypothesis is corroborated by investigations that have shown an antioxidant enzyme imbalance associated with AD primarily involving MnSOD. Previous clinical findings have reported upregulation of antioxidant enzymes, i.e., MnSOD, in disease progression [119]. In fact, Swomley et al. [120] described alterated blood antioxidant markers in AD, including increased erythrocyte Cu/ZnSOD and upregulated lymphocyte MnSOD messenger RNA (mRNA). There are several explanations for increased MnSOD in AD. MnSOD upregulation is a potential compensatory mechanism against elevated oxidative stress found in neural cells undergoing AD alteration. Increased mitochondrial O2 • could trigger a concomitant increase in MnSOD. The O2 • anion production via NADPH-oxidase (NOX) plays a role in a variety of neurological diseases, including AD [121]. Guix et al. [122] demonstrated increased ONOO (via O2 • –NO• reaction) using an in vitro model of neuronal aging during their investigation of inherited familial AD. Increased MnSOD can also increase H2O2 and contribute to oxidative stress and AD pathogenesis. H2O2 is a known stimulator of β-amyloid secretion. β-Amyloid is a metal-binding protein and copper, zinc, and iron promote oligomer formation. In rat brain, decreased MnSOD triggered increased β-amyloid deposition in the parenchyma and increased amyloidosis in the vasculature. It is likely that MnSOD imbalance has a central role in AD pathogenesis (Fig. 4). It should be noted that copper and iron are redox active and can generate ROS via the Fenton reaction, a chemical reaction between H2O2 and transition metals, and the Haber–Weiss reaction [123]. Increased oxidative stress in AD is correlated to increased iron, copper, protein, and DNA oxidation and enhanced lipid peroxidation in the brain [124]. Neurodegeneration has been speculated to result from the interplay between environmental and genetic factors. ROS-related neurodegeneration appears associated with certain genetic mutations that create susceptibility to neurologic pathology [113].


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Figure 4 The possible relationship of increased superoxide (O2 • ) production to the β-amyloid accumulation. The increased O2 • concentration leads to hydrogen peroxide (H2O2) content in the cytosol. The increased concentration of H2O2 boosts the production of the harmful hydroxyl radical (OH•) due to iron (Fe2+)-mediated reaction (Fenton). The harmful OH• induces lipid, protein, and DNA oxidation, leading to neuronal production of β-amyloid protein.

Genetic SNP affecting MnSOD efficiency could help us understand the relevance of this antioxidant enzyme imbalance in AD. Wiener et al. [125] investigated the potential association between four SNPs and AD. This study corroborated the relevance of MnSOD imbalance in AD. The results were obtained using family-based association testing results in the National Institute of Mental Health-AD Genetics Initiative set of families. Among the SNPs investigated, MnSOD Ala16Val SNP appeared to play a key role. The relevance of H2O2 imbalance in AD was additionally corroborated by studies involving GPx SNP. A population study performed by Hong et al. [126] described an association between GPx activity-decreasing SNP and AD. Similar results were also found by Maes et al. [127]. Parkinson’s disease (PD) is another important neurodegenerative disorder associated with aging. Pathogenesis is directly related to the selective loss of dopaminergic neurons in the substantia nigra pars compacta and the degeneration of projecting nerve fibers in the striatum. Although 10% of PD cases can be explained by specific genetic mutations, the mechanism responsible for 90% of PD is unknown. In both scenarios, clinical symptoms

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involve tremor and a profound loss of motor control. PD progression is also accompanied by perturbations in specific biochemical pathways, including loss of mitochondrial function [128]. In PD, oxidative stress contributes to dopaminergic neuron degeneration due to mitochondrial dysfunction and microglial activation which produces NO• and O2 • during neuro-inflammatory response [128]. Experimental models, i.e., DJ-1 knockouts in mice, demonstrated that loss of this protein increased H2O2 in brain [129]. Complementary studies also reported that DJ-1 inactivation increased MnSOD, thus explaining the concomitant increase in H2O2[130]. In fact, MnSOD is specifically located in brain striatum and substantia nigra. It has also been shown that MnSOD, via the transcription factor FoXO, can prevent the loss of dopaminergic neurons in a Drosophila melanogaster Parkinson’s model (PINK-null) [131]. An investigation performed by Wang et al. [132] found that the AA genotype of the MnSOD Ala16Val SNP was significantly associated with PD in 405 Taiwanese patients. As previously mentioned, the Ala variant has been shown to improve MnSOD-processing efficiency, resulting in increased MnSOD mRNA and protein tetramers in the mitochondria. However, studies performed by Singh et al. [133] and Grasbon-Frodl et al. [134] were contradictory, suggesting gene–environment or gene–gene interactions between PD and MnSOD. This hypothesis is corroborated by a study by Fong et al. [135], which found an association between the Ala allele and PD in subjects exposed to pesticide. Similar to AD, increased MnSOD enzyme efficiency could increase vulnerability to development of PD. Ischemic stroke results from obstruction within vessels supplying blood to the brain. This phenomenon is generally associated with atherosclerosis caused by fatty deposits lining on the vessel walls. In ischemic stroke, i.e., “cerebrovascular accident,” interruption of blood circulation in the ischemic vessel causes a bioenergetic collapse [136]. Clinical management of ischemia involves the administration of pharmacological agents to dissolve the clot and restore blood flow [137]. Unfortunately, this process causes a secondary wave of ROS generation from enzymes such as xanthine oxidase during reperfusion leading to increased O2 • . Because MnSOD efficiency is crucial to avoid cerebral damage, it is important to clarify its role in O2 • mediated pathways. In MnSOD knockouts, lack of this antioxidant enzyme exacerbated ischemic brain damage via increased oxidative stress and DNA oxidation [138]. Another study performed by Huang et al. [139] evaluated the protective effect of a MnSOD-mimetic compound, MnTm4PyP. In this


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study, mice with middle cerebral artery occlusion were used. Animals pretreated with MnTm4PyP decreased oxidative stress and apoptosis in ischemic brain cells and tissues. As such, MnSOD could be an effective therapeutic target in ischemic stroke prevention. Psychiatric diseases affect a large number of individuals worldwide. Among these, schizophrenia is a devastating disorder present in 1% of the population. Because neural cells are highly susceptible to oxidative damage [140], a number of studies have suggested a role for oxidative stress in the development of schizophrenia. Oxidative stress involving ROS-mediated damage in the CNS can result from inefficient antioxidant defense and/or increased ROS [141]. Studies have indicated that the abnormal activity of critical antioxidant enzymes, such as MnSOD, might be a risk factor for schizophrenia and/or tardive dyskinesia (TD). In fact, previous studies have suggested that schizophrenic subjects have increased O2 • versus healthy individuals [142,143]. Flatow et al. [144] performed a meta-analysis of oxidative stress in schizophrenia that evaluated clinical status and antipsychotic treatment after an acute exacerbation of psychosis. Based on the 44 studies, the authors found that total antioxidant status was associated with psychotic state, i.e., plasma level was significantly decreased in patients who presented with first episode psychosis (FEP). In contrast, total antioxidant status was significantly increased in patients undergoing antipsychotic treatment for acute exacerbations of psychosis. SOD was decreased in FEP and acutely relapsed patients. Decreased antioxidant enzymes, i.e., SOD, was also described by Tsai et al. [145] in schizophrenia. A number of studies evaluated the relationship between MnSOD Ala16Val SNP and schizophrenia. Unfortunately, most data indicated that this SNP did not directly affect susceptibility although the Val allele was correlated with negative schizophrenic symptoms and TD in some populations. A recent study by Zhang et al. [146] also described the association between the MnSOD Ala allele and cognitive impairment in schizophrenia. Due to its dual role in the CNS, lack of association between schizophrenia and this SNP may result from gene–gene interaction, disease stage or associated symptoms. It should be pointed out that pharmacologic treatment could also influence these results. MnSOD imbalance itself may contribute to this disorder and/or its symptoms. The enzyme may, however, play a role in other prevalent psychiatric diseases, i.e., depression and mood disorders. Given their protective effect against brain injury and neuronal death, deficiency of antioxidant enzymes may contribute to other mood disorders such as

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major depressive disorder (MDD) and bipolar I disorder (BD) [147]. Evidence has shown that mood stabilizers or antidepressants can affect the activity of various antioxidant enzymes, resulting in altered expression in brain or peripheral blood concentration [148,149]. Recurrent depressive disorder (rDD) is among the most commonly diagnosed disabling diseases. This condition appears to involve immuneinflammatory and oxidative/nitrosative stress. However, studies investigating the association between MnSOD levels and rDD have been contradictory. Although increased SOD in rDD was found in some studies [150], others found decreased SOD during the bipolar disorder depressive phase [151]. Genetic studies demonstrated a potential association between the MnSOD Ala16Val SNP and depression or mood disorders. Gałecki et al. [152] reported that the Val allele was associated with the development and course of depression. Curmucu et al. [153] also investigated the etiopathogenetic role of MnSOD and enzyme-associated SNP in MDD and BD. Although these authors did not find an association with the MnSOD Ala16Val SNP, the study was limited by low number of participants (n < 100).

4.2. Metabolic-related conditions The liver plays a key role in systemic metabolic modulation via glycogen storage, gluconeogenesis, and the Cori cycle. Given its major metabolic role, it has been suggested that ROS-mediated damage may play a major role in liver disease, i.e., steatosis, hereditary hemochromatosis (HHC), hepatocellular carcinoma (HCC), and alcohol-related conditions [154–156]. Increased ROS-mediated damage resulting in lipid peroxidation has been observed in nonalcoholic fatty liver disease, alcoholic liver disease, and steatosis [156,157]. Oxidative stress has been reported as the most relevant and fibrogenesis-associated pathology in HHC [155]. Fibrosis in hepatitis C virus (HCV)-infected liver is associated with increased malondialdehyde (MDA), 8-OhdG, and 8-isoprostrane [158–160]. Similarly, electron paramagnetic resonance indicated that ROS increased two to fivefold in the liver chronic hepatitis C (CHC) patients [161]. Biochemical assays demonstrated increased oxidative stress markers in lymphocytes of chronic and HCV patients [162]. ROS-related damage implicated in liver disease is associated with diminished oxidative capacity of HCV patients [163]. Oxidative stress is known to be one of the main HCV-related hepatocyte proliferative mechanisms leading to HCC.


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Mitochondria are mediators of receptor-induced cell death in hepatocytes [164,165]. The mitochondrial-related death pathway may be triggered by different stimuli including increased ROS production [165]. Apoptotic pathways include release of proteins, i.e., cytochrome c (Cyt c), Smac/ DIABLO, apoptosis-inducing factor (AIF), and endonuclease G, normally located in the mitochondrial intermembrane space [166,167]. Release of these proteins results in cytosolic protease activation or nuclear translocation, causing apoptosis, DNA fragmentation, and chromatin condensation (Fig. 5) [164]. Increased circulating O2 • has been found in decompensated cirrhosis [169]. Hepatic steatosis has also been implicated in mitochondrial

Figure 5 Release of mitochondrial apoptotic factors. The cytochrome c (Cyt c) reaches the cytosol and interacts with the apoptosis protease-activating factor-1 (Apaf-1) which produces an apoptosome for caspase-9 activation; the caspase-9 activation ultimately induces caspase-3-mediated cell death. The X-linked inhibitor of apoptosis protein (XIAP) is able to block caspases-3 and -9 action, although the second mitochondriaderived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point (Smac/DIABLO) and high temperature requirement protein A2 and stress-regulated endoprotease (HtrA2/Omi) neutralizes XIAP. The apoptosis-inducing factor (AIF) is another apoptogenic molecule which is also released from the mitochondria. The AIF translocates into the nucleus and triggers DNA fragmentation and chromatin condensation. Adapted from Ref. [168].

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dysfunction with concomitant ROS formation leading to lipid peroxidation, cytokine induction, and steatohepatitis [154]. MnSOD activity is higher in liver versus other human tissues, i.e., brain and skeletal muscle [170]. In viral hepatitis, increased MnSOD represents an adaptive response to the oxidative stress-related pathways (infection persistence and damage progression) [171]. Additionally, viruses may alter mitochondrial function, inducing oxidative stress through organelle association and lead to the activation of different apoptosis and proliferation transcription factors, such as p38, MAPK, and JNK (via AP-1), that upregulates hepatic MnSOD [171,172]. Given its mitochondrial location, MnSOD may be a marker of hepatic oxidative stress-induced disorders [173]. Increased MnSOD has been proposed as a marker for early HCC [173] and chronic hepatitis [174]. Child-Pugh class A liver cirrhosis patients also have increased serum MnSOD [172]. MnSOD may be induced by different stimuli, such as ROS, cytokines, and ethanol [175] and this upregulation decreased cellular O2 • [176] and ONOO produced by NO•–O2 • reaction that may play an important role in alcohol-induced liver injury [177]. As such, MnSOD upregulation may not be exclusively related to ROSmediated cell adaptation. It may be relevant, however, in cell proliferation and tumor growth regulation via O2 • dismutation [172]. Excessive oxidative stress has been implicated as a major factor in the onset of diabetes [23], which may lead to myocardial ischemia and reperfusion injury [178]. It has been suggested that the upstream event for development of diabetes involves mitochondrial ROS overproduction [12]. In fact, O2 • production is considered a causal link between increased glucose and development of vascular complications [179,180]. Normalization of high glucose-cultured endothelial cells by MnSOD overexpression suggested that mitochondrial respiration acts as a major source of oxidative stress in diabetes [105,181]. Currently, it is known that several obesity-related conditions, i.e., atherosclerosis, are associated with increased ROS production. Oxidative stress and redox status have been studied in young populations to determine the possible metabolic modulation of the O2 pathway. Isoprostane was increased in obese children with increased blood pressure [182]. Levels were positively correlated with metabolic risk factors in severe childhood obesity [24]. MDA was inversely correlated with high-density lipoprotein (HDL) cholesterol in these children and HDL was negatively correlated with advanced oxidation protein products. Similarly, childhood obesity affected redox status markers, such as reduced plasma α-tocopherol and ascorbic acid


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[183,184]. Zhu et al. [184] found decreased SOD and CAT activities in obese children. Only one study investigated the influence of Ala16Val on childhood obesity [185]. Although obesity was not associated with this SNP, environmental factors were not considered. The Ala16Val SNP has been associated with different metabolic-related conditions. The Val allele and Val/Val genotype have been associated with nephropathy in diabetic patients [186,187]. In contrast, the Val/Val genotype was associated with increased risk for diabetic nephropathy when controlled for gender [188]. Val allele carriers and the homozygous Val genotype were associated with a higher risk of neuropathy in diabetics [189] and the Val/Val genotype was associated with diabetic retinopathy [190]. The Ala allele and homozygous Ala genotype were found in another diabetic retinopathy population [191]. Interestingly, the homozygous Val/Val genotype has also been correlated with poorer control in diabetics with or without macroangiopathy [192]. Recently, a combination of the Ala16Val with GPx1 and CAT SNPs has been associated with increased plasma triglyceride in type 2 diabetes mellitus and diabetic CAD [193]. Previous clinical studies from our research group have described the association between the Val allele and metabolic diseases associated with atherosclerotic risk, i.e., hypercholesterolemia [194] and obesity [195]. The Val allele was also associated with increased oxidized low-density lipoprotein (ox-LDL) especially in type 2 diabetics [196]. Increased inflammatory cytokines have also been noted [197]. It is uncertain if these findings can be applied to children. Future genetic studies should consider the possible role of the MnSOD Ala16Val SNP in childhood obesity.

4.3. Cardiovascular system Mitochondrial ROS production has been implicated in several cardiovascular-related disorders, i.e., atherosclerosis, hypertension, and diabetes [21]. Oxidative stress due to increased O2 • has been demonstrated in peripheral blood vessels during hypertension [22]. Consequently, hypertension increases vascular production of O2 • leading to inactivation of NO•-mediated endothelium-dependent vasodilatation (Fig. 6) [199]. The myocardium is equipped with endogenous enzymatic and nonenzymatic antioxidant systems capable of metabolizing ROS generated during normal cellular activity [200]. Evidence of increased myocardial oxidative stress and

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Figure 6 Cardiovascular disease-related factors and mitochondrial ROS production. The increased superoxide (O2 • ) production leads to a cascade of ROS production and redox state disruption. While the combination of O2 • with nitric oxide (NO•) impairs vasodilatation, its reaction with peroxynitrite (ONOO) leads to MnSOD inactivation and oxidation of low-density lipoprotein (ox-LDL). At this stage, a mitochondrial dysfunction due to increased membrane permeability (Δψ) may take place, with hydroxyl radical (OH•) formation due to iron (Fe2+) release. These alterations increase cardiovascular (CVD)-related risk factors. Adapted from Ref. [198].

ROS production has been observed in animal models of heart failure and has been implicated in the pathogenesis of cardiac injury and the progression of heart failure [11]. Decreased MnSOD during acute to chronic phase disease development in infected murine myocardium has been reported [201]. Atherosclerosis is a complex disease process associated with risk factors including hypertension, hyperlipidemia, and genetic makeup [202,203]. Atherosclerosis can be considered a chronic inflammatory process with underlying abnormal redox state in the vascular cell wall [204,205]. As such, lipoprotein oxidation, especially LDL, is considered to be a key event in its pathogenesis [206–208]. Furthermore, cholesterol oxidation products (ChOx) have been reported as the major cytotoxic components of ox-LDL and stimulate cholesterol accumulation in vascular cells [208]. Fortunately, MnSOD overexpression inhibits atherosclerosis [209]. Several studies have used different MnSOD knockouts to elucidate its role in cardiovascular-related diseases. Notably, MnSOD knockouts die prematurely from dilated cardiomyopathy within several weeks of birth


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and show increased hepatic lipid content and neurodegeneration [85,210,211]. Knockouts had substantial reduction in mitochondrial enzyme activity, i.e., complexes I–III and aconitase [212]. As a result, genomic DNA from knockouts had significant oxidative damage [213]. Similarly, an ApoE/ model demonstrated that MnSOD was responsible for an endothelial function-associated O2 • increase which caused mitochondrial damage. The same knockout model demonstrated mitochondrial dysfunction, increased mtDNA damage, and accelerated atherosclerosis. Thus, MnSOD has been strongly implicated in endothelial function via NO• and ROS within mitochondria. In murine brain, intracerebroventricular MnSOD injection reduced angiotensin II-induced increases in heart rate, blood pressure, and drinking behavior [214]. Additionally, the overexpression of MnSOD or a mitochondrially targeted mitoTEMPO SOD mimetic improved endothelial function, reduced hypertension and oxidative stress in angiotensin II or DOCA salt-induced hypertensive mice [215]. Moreover, it has been shown that pulmonary arterial hypertension is increased by the epigenetic attenuation of MnSOD [216]. An angiogenesis study revealed that MnSOD overexpression induced H2O2 production which stimulated endothelial cell sprouting and neovascularization [217]. Furthermore, it has been reported that vascular endothelial growth factor (VEGF) induced MnSOD upregulation in human cell culture, which may represent a ROS-induced H2O2 mechanism to enhance angiogenesis [218]. These findings indicate the relevant role for MnSOD in mitochondrial O2 • detoxification. The mechanisms implicated in heart failure progression suggest that ROS plays a major role [219,220]. Pericardial fluid and peripheral blood ROS markers have been detected in heart failure [221–223] and hypertension [22]. The Ala16Val SNP has been associated with high intima media thickness and plasma LDL concentration in hypertensive Val carrier females [207]. Ala carriers were more prone to arsenic-related hypertension [224]. Cardiomyopathy was more prevalent in Val carriers with unrelated hemochromatosis. Ala/Val and Val/Val exhibited increased ox-LDL suggesting that Val carrier status was an independent factor for ox-LDL [196]. The Ala variant decreased risk for coronary artery disease and acute myocardial infarction by upregulated MnSOD and reduced ox-LDL apoptosis [225]. The Val allele has also been associated with vasospastic angina pectoris with the Val/Val genotype as an independent risk factor [226]. Cardiogenic shock has been correlated with the Val allele in dilated cardiopathy [227].

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5. ENVIRONMENTAL FACTORS, GENETICS, AND MnSOD MODULATION Despite epidemiologic evidence, the role of Ala16Val SNP on MnSOD modulation remains unclear [101]. Studies have evaluated this relationship in conjunction with environmental factors known to influence ROS, i.e., smoking and alcohol intake, for example [228–232]. Ambrosone et al. [32] demonstrated that epigenetic factors may be responsible. In this study, Ala homozygous females with low antioxidant intake had increased risk of breast cancer. Studies concerning the role of diet are, however, conflicting. Although the Ala allele and Ala homozygous genotype were correlated to low antioxidant intake in breast cancer [32,233], the Val/Val genotype increased the prevalence of aggressive prostate cancer in males with increased iron intake [234]. To provide better experimental control, in vitro assays may serve as a viable option. For example, one study found that 6 weeks of antioxidant supplementation decreased the Ala alleleassociated DNA damage in isolated human lymphocytes [235]. These preliminary findings clearly indicate the need for more comprehensive and better controlled in vitro and in vivo studies.

5.1. Exercise, oxidative stress, and health: Evidence for MnSOD involvement The health benefits of regular exercise are well documented [236,237] and include both psychologic and physiologic benefits to a variety of disorders such as heart disease, hypertension, and diabetes [238–242]. In fact, regular exercise has long been associated with improved lipid profile (see Ref. [243] for a review) and endothelial function in type 1 diabetes [244]. In a recent report, type 2 diabetics showed lipid profile benefits from aerobic, resistance, or combined training [245]. Davis et al. [242] found that lowand/or high-intensity aerobics induced positive effects on insulin resistance and adiposity in obese children thus decreasing type 2 diabetesassociated risks. Exercise reduces primary and secondary cardiovascular events [246] by enhancing cardiorespiratory fitness. After 8–12 weeks of aerobic training, subjects with resistant hypertension had decreased blood pressure and increased performance [247]. Exercise has also been demonstrated to decrease blood pressure in subjects with low responsiveness to medical


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treatment [247]. The authors concluded that exercise should be included as a part of the therapeutic approach in those individuals with resistant hypertension. Patients with CAD demonstrated improved maximal exercise capacity, ventilation threshold, and muscular performance following endurance and combined endurance/resistance training [248]. Interestingly, the latter group was also characterized by increased HDL. In a recent review of CAD and metabolic syndrome, Otani [249] suggested that aerobic exercise may be the most effective nonpharmacologic tool for metabolic syndrome management and this improvement occurs largely through oxidative stress modulation. It is well known that physical exercise increases the antioxidant capacity of the exercised muscle, which in turn induces positive adaptive stimuli of redox status [1,31,35,250,251]. The effect of physical exercise on redox balance and MnSOD has been the subject of many investigations. Studies have reported increased MnSOD after exercise in general [252–256] and under different experimental conditions [253,254,257–261]. Recently, MnSOD mRNA expression was shown to be upregulated by exercise [261–263]. Thus, there is considerable evidence that exercise training may result in positive MnSOD modulation through redox-sensitive pathways (Fig. 7). 5.1.1 Exercise and genetics: Where nature and nurture meet The advent of molecular biology introduced a new field in sport sciences: molecular exercise physiology as presented by Harridge and Spurway [264]. Over the last decades, exercise physiologists have studied the potential influence of genetics on exercise outcomes and the relationship among

Figure 7 Effects of regular moderate intensity exercise on mitochondrial quality. The regular exercise increases the antioxidant defenses and thus reducing oxidative stress. This positive modulation is reflected on an enhanced redox status, leading to a decrease on the risk of cardiovascular diseases, neurological and metabolic related. On the opposite, sedentarism disrupts the redox state across decreased antioxidant defenses, and it has been long related to prevalence of noncommunicable diseases, such as cardiovascular- and metabolic-related conditions.

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SNP and exercise performance. The role of angiotensin-converting enzyme in exercise performance related to the cardiovascular system has been extensively investigated [265,266]. Type V (CLOA5A1) and VI collagen (COL6A1) SNPs were evaluated with respect to their relationship to endurance [267–269]. The α-actinin 3 gene (ACTN3) SNP and its association with strength exercises have also been studied [270,271]. For additional information, the reader is referred to an excellent review on exercise-related benefits and genetic background [272]. Despite their apparently key role, studies to assess the influence of SNP on exercise-induced antioxidant enzyme modulation remain relatively scarce. Antioxidant enzyme SNPs may imbalance oxidative stress and antioxidant defense following exercise. The role of Ala16Val SNP in exercise has been recently studied. DNA damage was increased in homozygous Ala genotype runners [273], whereas the Val allele was associated with increased muscle damage in females [274]. In our experience, exercise-induced MnSOD mRNA and enzyme activity in homozygous Ala genotypes and Val/Val carriers showed decreased thiol content [275]. Additionally, the Ala/Ala genotype showed increased MnSOD and dose-dependent activity in the Ala allele carriers, which was reflected by unchanged thiol content [275]. Heterozygous Ala16Val carriers resulted in decreased DNA damage and lipid peroxidation with carotenoid-enriched oil supplementation following exercise [276]. Leukocytes of healthy/trained subjects had different responses depending on Ala/Val SNP [277]. Overall, these results indicate that environmental factors may differentially modulate the response of SNPs to oxidative stress. Unfortunately, studies on the effect of exercise training on MnSOD Ala16Val SNP modulation have not been performed to date. As such, whether moderate exercise training would help prevent disease-associated risks in different Ala16Val carriers remains an open question.

6. CONCLUSIONS Oxidative stress has been long associated with disease etiology. Increased ROS production is known to mediate a few signaling pathways, the end products of which may alter homeostasis through metabolic disruption. Lipid peroxidation, protein carbonylation, and DNA damage have all been found in different disease-related settings, i.e., neuronal- and metabolic-related conditions. Increased ROS production has been reported in atherosclerosis and PD. Fortunately, humans have a highly specialized


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antioxidant system that includes both direct ROS quenchers and enzymes. The enzymatic antioxidant system depends on the powerful MnSOD, a mitochondrial enzyme, which is the first line of ROS defense in aerobes. The Ala16Val SNP of this enzyme has been shown to differentially modulate the enzyme activity within several disease-related conditions, such as neural and cardiovascular pathologies. Exercise, which is also a potent MnSOD modulator, has been observed to influence the health of these chronic and neurologic diseases. Exercise has also been shown to modulate MnSOD Ala16Val response to stress in different study populations. However, the role of exercise training to promote antioxidant adaptation via MnSOD Ala16Val modulation remains unanswered. Elucidation of the interplay between environmental and genetic factors in disease-related conditions may help to identify alternative strategies to maintain, prevent, and in some cases treat chronic disease.

ACKNOWLEDGMENTS The authors are indebted to Leonardo Barili Brandi for technical support with figure editing. The Laborato´rio de Biogenoˆmica is funded by CNPq, FAPERGS, CAPES, and FAPEAM. CIBERehd is funded by the Instituto de Salud Carlos III, Spain.

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Manganese superoxide dismutase and oxidative stress modulation.

Oxidative stress is characterized by imbalanced reactive oxygen species (ROS) production and antioxidant defenses. Two main antioxidant systems exist...
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