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From Guilherme Bresciani, Ivana Beatrice Mânica da Cruz and Javier González-Gallego, Manganese

Superoxide Dismutase and Oxidative Stress Modulation. In: Gregory S. Makowski, editor, Advances in

Clinical Chemistry, Vol. 68, Burlington: Academic Press, 2015, pp. 87-130.

ISBN: 978-0-12-802266-5

© Copyright 2015 Elsevier Inc.

Academic Press

Provided for non-commercial research and educational use only. Not for reproduction, distribution or commercial use.

CHAPTER FOUR

Manganese SuperoxideDismutase and Oxidative StressModulationGuilherme Bresciani*,1, Ivana Beatrice Manica da Cruz†,Javier González-Gallego{*Facultad de Ciencias de la Salud, Universidad Autonoma de Chile, Temuco, Chile†Laboratorio de Biogenomica, Departamento de Morfologia, Universidade Federal de Santa Maria,Santa Maria, Brazil{Institute of Biomedicine (IBIOMED) and Centro de Investigacion Biomedica en Red de EnfermedadesHepaticas y Digestivas (CIBERehd), University of Leon, Leon, Spain1Corresponding author: e-mail address: guilhermebresciani@gmail.com

Contents

1. Introduction 892. Oxidative Stress: A Brief Review 91

2.1 Mitochondrial role in energy production 912.2 ROS generation and effects in the organism 92

3. Superoxide Dismutase in Antioxidant Defense 963.1 Antioxidant defense 963.2 Superoxide dismutase 97

4. MnSOD and Oxidative Stress Modulation 994.1 Nervous system 1004.2 Metabolic-related conditions 1054.3 Cardiovascular system 108

5. Environmental Factors, Genetics, and MnSOD Modulation 1115.1 Exercise, oxidative stress, and health: Evidence for MnSOD involvement 111

6. Conclusions 113Acknowledgments 114References 114

Abstract

Oxidative stress is characterized by imbalanced reactive oxygen species (ROS) produc-tion and antioxidant defenses. Two main antioxidant systems exist. The nonenzymaticsystem relies on molecules to directly quench ROS and the enzymatic system is com-posed of specific enzymes that detoxify ROS. Among the latter, the superoxide dis-mutase (SOD) family is important in oxidative stress modulation. Of these,manganese-dependent SOD (MnSOD) plays a major role due to its mitochondrial loca-tion, i.e., the main site of superoxide (O2

•�) production. As such, extensive research has

Advances in Clinical Chemistry, Volume 68 # 2015 Elsevier Inc.ISSN 0065-2423 All rights reserved.http://dx.doi.org/10.1016/bs.acc.2014.11.001

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focused on its capacity to modulate oxidative stress. Early data demonstrated the rel-evance of MnSOD as an O2

•� scavenger. More recent research has, however, identifieda prominent role for MnSOD in carcinogenesis. In addition, SOD downregulationappears associated with health risk in heart and brain. A single nucleotide polymor-phism which alters the mitochondria signaling sequence for the cytosolic MnSOD formhas been identified. Transport into the mitochondria was differentially affected by allelicpresence and a new chapter in MnSOD research thus begun. As a result, an ever-increasing number of diseases appear associated with this allelic variation includingmetabolic and cardiovascular disease. Although diet and exercise upregulate MnSOD,the relationship between environmental and genetic factors remains unclear.

ABBREVIATIONSAD 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 oxi-

dative 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 prop-

agation 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]. Inter-

mediates in the O2 reduction process are called free radicals—molecules that

contain an unpaired electron (radical) and are capable of independent exis-

tence (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 metab-

olites 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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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 pro-

duction by oxidative metabolism and other sources may cause distress lead-

ing 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 fewROS-relatedmolecular 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]. Neverthe-

less, 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 polymor-

phisms (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 promi-

nence in recent years.

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

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2. OXIDATIVE STRESS: A BRIEF REVIEW

The O2 molecule was introduced into earth’s atmosphere approxi-

mately 2–3 billion years ago due to the evolution of O2-releasing photo-

synthetic 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 combus-

tion 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 elec-

tron 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 pro-

duction 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 disor-

ders [25,26].

2.1. Mitochondrial role in energy productionMitochondria are ubiquitous organelles that perform crucial cellular func-

tions 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 intracel-

lular 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 ETCwith 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 gen-

erate ATP [30].

During this process, however, 2–5% of O2 undergoes univalent reduc-

tion generating O2•�[31], the first ROS produced by this pathway [32]. As

such, ROS are atoms or molecules with one unpaired electron in their out-

ermost 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•� dur-

ing cell respiration can give rise to other ROS.

2.2. ROS generation and effects in the organismROS can be produced by other processes including catecholamine auto-

oxidation, 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 oxi-

dase 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 dis-

mutation of O2•� can also produce H2O2[14]. Reaction of free iron

(Fe2+) and H2O2 generates hydroxyl radical (OH•), which appears respon-

sible 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 microor-

ganisms, 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. NADHcollects electrons from the oxygen molecules (O2). The electrons subsequently flowthrough the mitochondrial electron transport chain (ETC) complexes for ATPresynthesis. A small amount of the O2 undergoes an incomplete reduction giving riseto the superoxide anion (O2

•�), the first ROS within the aerobic organisms. After, themanganese-dependent superoxide dismutase (MnSOD) dismutates the O2

•� intohydrogen peroxide (H2O2) and O2; the H2O2 is further neutralized by the glutathioneperoxidase (GPx) into H2O with glutathione (GSH) as a substrate. Equally, H2O2 maybe also converted into the hazardous hydroxyl radical (OH•) through Fenton reactionwith iron (Fe2+). Outside the mitochondria, the O2 can also be converted into O2

•�

through an NADPH-oxidase reaction with nicotinamide adenine dinucleotide phos-phate (NADPH) as substrate. Further, the copper–zinc-dependent superoxide dismutase(Cu/ZnSOD) dismutates the O2

•� in the membrane interspace while the same reactiontakes place in the extracellular milieu by the extracellular superoxide dismutase(ecSOD). Here, the H2O2 is also neutralized by the GPx, although catalase (CAT) alsoreacts with this ROS. The O2 molecule may also give rise to the nitric oxide (NO•) acrossa 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]. Per-

oxynitrite (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 neuro-

vascular 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 peroxidationLipid peroxidation is a physiologic process primarily affecting cell mem-

branes. 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., lyso-

somes, may result in the release of phospholipases and other enzymes that

promote additional membrane degradation [50]. Increased membrane per-

meability results in facilitated ion influx that activates phospholipases, thus

promoting additional permeability [51].

2.2.2 Protein and enzyme oxidation and glycosylationROS 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 car-

bonylation 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 inac-

tive, inducing relevant physiologic alterations. Damage to channel proteins

can lead to disrupted cell function due to ion imbalance [56].

2.2.3 Metabolic disruptionMitochondrial ETC complexes I and III are the primary sites of ROS pro-

duction 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 physiolog-

ically 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 acidsWhen antioxidant defenses are overwhelmed, DNA can suffer direct ROS-

mediated 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 defenseOrganisms 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 integ-

rity. The nonenzymatic system is composed of a myriad of antioxidant mol-

ecules 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 1.15.1.1,

superoxide:superoxide oxidoreductase), glutathione peroxidase (GPx, EC

1.11.1.9, glutathione:hydrogen peroxide oxidoreductase), and catalase

(CAT, EC 1.11.1.6, hydrogen peroxide:hydrogen peroxide oxidoreduc-

tase) [68]. These enzymes are compartment specific and regulated geneti-

cally [69]. SOD dismutates O2•� into H2O2 to avoid accumulation to

toxic level [70]. The primary mechanism to eliminate H2O2 and lipid per-

oxides in the cytosol and mitochondria is catalyzed by GPx, which uses glu-

tathione (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 reduceH2O2, isoforms differ in tissue expres-

sion 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 bio-

chemical pathways. Despite its ubiquitous distribution, CAT is primarily

localized in peroxisomeswhich useO2•� 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 dismutaseSOD is the first line of defense in the antioxidant enzyme repertoire, cata-

lyzing O2•� anion dismutation into O2 and H2O2. This remarkable discov-

ery 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 mito-

chondrial 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 disor-

ders 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 manga-

nese as a cofactor. MnSOD, the only isoform present in mitochondria, is

considered essential for aerobic survival [83,84]. Genetic studies have rev-

ealed that the null homozygous mutation (MnSOD�/�) is lethal, whereasknockouts of Cu/ZnSOD and GPx are not [85]. MnSOD-knockout

mice have severe mitochondrial damage, decreased GSH, increased 8-

hydroxy-20deoxyguanosine (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 rel-

evant changes at the molecular level, especially in humans. Increased under-

standing of the role of the environment in the molecular biology of

organisms will be discussed below.

3.2.1 MnSOD and the Ala16ValSNPThe 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 func-

tion [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 anti-

oxidant 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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amino acid substitution results in a distinct conformational change (β [beta]-sheet to α [alpha]-helix) in this region which modifies the mitochondrial

import ofMTS-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 cardi-

opathy [105], cell signaling death in liver [106], and restored redox balance

in the skeletal muscle following exercise [107]. ROS are frequently associ-

ated with pathophysiology and an increasing number of diseases are associ-

ated with ROS activity as an etiologic agent or contributing factor [108].

Several studies have shown that MnSOD induction can protect against

Figure 3 Manganese-dependent superoxide dismutase (MnSOD) content in the mito-chondria according to different Ala16Val precursors. While the alanine (Ala) precursor iscorrectly transported across both mitochondrial membranes (MTS-Ala), the valine (Val)precursor is partially arrested in the inner membrane (MTS-Val). The increased MnSODcontent afforded by the Ala precursor is translated into a more efficient superoxide(O2

•�) detoxification, whereas the Val precursor leads to O2•� accumulation in the mito-

chondria. Adapted from Ref. [101].

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neurotoxic conditions [102], cardiomyopathy [105,109], and diabetic disor-

ders [110,111]. Environmental and/or genetic factors that modulate antiox-

idant 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 increas-

ing number of studies have investigated the relationship of the Ala16Val

SNP with neural, metabolic, and CAD.

4.1. Nervous systemAlthough 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, polyunsatu-

rated 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 phys-

iologic conditions. O2•� and H2O2 production/catalysis is particularly

important to the central nervous system (CNS) and peripheral nervous sys-

tem (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 impor-

tant 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 con-

stituents [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 ther-

apy [117]. Significant heterogeneity in research design, differential control

of confounders, insufficient measures of cognitive performance, and diffi-

culty 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 clin-

ical 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] dem-

onstrated 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 secre-

tion. β-Amyloid is a metal-binding protein and copper, zinc, and iron pro-

mote oligomer formation. In rat brain, decreased MnSOD triggered

increased β-amyloid deposition in the parenchyma and increased amyloid-

osis in the vasculature. It is likely thatMnSOD 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 tran-

sition metals, and the Haber–Weiss reaction [123]. Increased oxidative stress

in AD is correlated to increased iron, copper, protein, andDNAoxidation 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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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 Insti-

tute 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 disor-

der 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

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 produc-tion 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 produc-tion of β-amyloid protein.

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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 neu-

rons 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 interac-

tions 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 ische-

mic 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. InMnSOD 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 ther-

apeutic 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 dam-

age [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 oxi-

dative 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 cor-

related 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 dis-

order 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 immune-

inflammatory andoxidative/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 SNPanddepressionormooddisorders.Gałecki et al. [152] reported

that the Val allele was associated with the development and course of depres-

sion. 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 associationwith theMnSODAla16Val SNP, the study

was limited by low number of participants (n<100).

4.2. Metabolic-related conditionsThe 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), hepatocel-

lular 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 rel-

evant and fibrogenesis-associated pathology in HHC [155]. Fibrosis in hep-

atitis C virus (HCV)-infected liver is associated with increased

malondialdehyde (MDA), 8-OhdG, and 8-isoprostrane [158–160]. Simi-

larly, electron paramagnetic resonance indicated that ROS increased two

to fivefold in the liver chronic hepatitis C (CHC) patients [161]. Biochem-

ical 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 hepa-

tocyte proliferative mechanisms leading to HCC.

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Mitochondria are mediators of receptor-induced cell death in hepato-

cytes [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 transloca-

tion, 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) reachesthe cytosol and interacts with the apoptosis protease-activating factor-1 (Apaf-1) whichproduces an apoptosome for caspase-9 activation; the caspase-9 activation ultimatelyinduces 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 mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a lowisoelectric point (Smac/DIABLO) and high temperature requirement protein A2 andstress-regulated endoprotease (HtrA2/Omi) neutralizes XIAP. The apoptosis-inducingfactor (AIF) is another apoptogenic molecule which is also released from the mitochon-dria. The AIF translocates into the nucleus and triggers DNA fragmentation and chro-matin condensation. Adapted from Ref. [168].

106 Guilherme Bresciani et al.

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dysfunction with concomitant ROS formation leading to lipid peroxida-

tion, 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 acti-

vation 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 serumMnSOD [172]. MnSODmay 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

•� reac-

tion that may play an important role in alcohol-induced liver injury [177].

As such, MnSOD upregulation may not be exclusively related to ROS-

mediated 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 reperfu-

sion injury [178]. It has been suggested that the upstream event for devel-

opment 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., ath-

erosclerosis, are associated with increased ROS production. Oxidative stress

and redox status have been studied in young populations to determine the

possible metabolic modulation of theO2 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].

MDAwas inversely correlated with high-density lipoprotein (HDL) choles-

terol in these children and HDL was negatively correlated with advanced

oxidation protein products. Similarly, childhood obesity affected redox sta-

tus 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 geno-

type was associated with increased risk for diabetic nephropathy when con-

trolled 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 asso-

ciation between the Val allele and metabolic diseases associated with athero-

sclerotic 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 cyto-

kines 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 systemMitochondrial ROS production has been implicated in several

cardiovascular-related disorders, i.e., atherosclerosis, hypertension, and dia-

betes [21]. Oxidative stress due to increased O2•� has been demonstrated in

peripheral blood vessels during hypertension [22]. Consequently, hyperten-

sion 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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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]. For-

tunately, 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

Figure 6 Cardiovascular disease-related factors andmitochondrial ROS production. Theincreased superoxide (O2

•�) production leads to a cascade of ROS production and redoxstate disruption. While the combination of O2

•� with nitric oxide (NO•) impairs vasodi-latation, its reaction with peroxynitrite (ONOO�) leads to MnSOD inactivation and oxi-dation of low-density lipoprotein (ox-LDL). At this stage, a mitochondrial dysfunctiondue 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].

109Manganese Superoxide Dismutase and Oxidative Stress Modulation

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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, geno-

mic 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 dysfunc-

tion, 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 targetedmitoTEMPOSODmimetic 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 attenu-

ation of MnSOD [216]. An angiogenesis study revealed that MnSOD over-

expression 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]. Cardiomy-

opathy 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 MnSODMODULATION

Despite epidemiologic evidence, the role of Ala16Val SNP on

MnSODmodulation remains unclear [101]. Studies have evaluated this rela-

tionship 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, con-

flicting. Although the Ala allele and Ala homozygous genotype were corre-

lated 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 allele-

associated 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 MnSODinvolvement

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 low-

and/or high-intensity aerobics induced positive effects on insulin resistance

and adiposity in obese children thus decreasing type 2 diabetes-

associated 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 hyperten-

sion. Patients with CAD demonstrated improvedmaximal 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 meetThe 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. Theregular exercise increases the antioxidant defenses and thus reducing oxidative stress.This positivemodulation is reflected on an enhanced redox status, leading to a decreaseon the risk of cardiovascular diseases, neurological and metabolic related. On the oppo-site, sedentarism disrupts the redox state across decreased antioxidant defenses, and ithas been long related to prevalence of noncommunicable diseases, such ascardiovascular- 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 exten-

sively investigated [265,266]. Type V (CLOA5A1) and VI collagen

(COL6A1) SNPs were evaluated with respect to their relationship to endur-

ance [267–269]. The α-actinin 3 gene (ACTN3) SNP and its association with

strength exercises have also been studied [270,271]. For additional informa-

tion, 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 mod-

ulation remain relatively scarce.

Antioxidant enzyme SNPs may imbalance oxidative stress and antioxi-

dant 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 disrup-

tion. 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 modulateMnSOD

Ala16Val response to stress in different study populations. However, the role

of exercise training to promote antioxidant adaptation viaMnSODAla16Val

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.

ACKNOWLEDGMENTSThe authors are indebted to Leonardo Barili Brandi for technical support with figure editing.

The Laboratorio de Biogenomica is funded by CNPq, FAPERGS, CAPES, and FAPEAM.

CIBERehd is funded by the Instituto de Salud Carlos III, Spain.

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