Hostname: page-component-7b9c58cd5d-dlb68 Total loading time: 0 Render date: 2025-03-16T10:05:54.668Z Has data issue: false hasContentIssue false

Protein undernutrition during development and oxidative impairment in the central nervous system (CNS): potential factors in the occurrence of metabolic syndrome and CNS disease

Published online by Cambridge University Press:  08 June 2016

D. J. S. Ferreira
Affiliation:
Neuropsychiatry and Behavior Science Graduate Program, Federal University of Pernambuco, Vitória de Santo Antão, Brazil
D. F. Sellitti
Affiliation:
Department of Medicine, Uniformed Service University of Health Science (USUHS), Bethesda, MD, USA
C. J. Lagranha*
Affiliation:
Neuropsychiatry and Behavior Science Graduate Program, Federal University of Pernambuco, Vitória de Santo Antão, Brazil Laboratory of Biochemistry and Exercise Biochemistry, Department of Physical Education and Sports Science, Federal University of Pernambuco, Vitória de Santo Antão, Brazil
*
*Address for correspondence: C. J. Lagranha, Rua Alto do Reservatório, s/n, Núcleo de Educação Física e Ciências do Esporte, Bela Vista, Vitória de Santo Antão 55608-680, PE, Brazil. (Email lagranha@hotmail.com)
Rights & Permissions [Opens in a new window]

Abstract

Mitochondria play a regulatory role in several essential cell processes including cell metabolism, calcium balance and cell viability. In recent years, it has been postulated that mitochondria participate in the pathogenesis of a number of chronic diseases, including central nervous system disorders. Thus, the concept of mitochondrial function now extends far beyond the common view of this organelle as the ‘powerhouse’ of the cell to a new appreciation of the mitochondrion as a transducer of early metabolic insult into chronic disease in later life. In this review, we have attempted to describe some of the associations between nutritional status and mitochondrial function (and dysfunction) during embryonic development with the occurrence of neural oxidative imbalance and neurogenic disease in adulthood.

Type
Review
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2016 

Introduction

In most eukaryotic cells, oxidative phosphorylation is the main source of energy, wherein a complex of membrane proteins located in the inner mitochondrial membrane is able to generate large amounts of energy stored in the form of adenosine triphosphate (ATP).Reference Skulachev 1 , Reference Leverve 2 Mitochondria are dynamic organelles whose roles in cell function originated in part from their prokaryotic ancestor (likely an α-proteobacterium) eons ago. The ability of those prokaryotes to provide energy to eukaryotes in an aerobic environment helped drive the evolution of those early one-celled eukaryotes into the multiplicity of multicellular forms that dominate life on earth today.Reference Hagberg, Mallard, Rousset and Thornton 3 Reference Ernster and Schatz 5

In addition to their important function as the ‘powerhouses’ of eukaryotic organisms,Reference Shaughnessy, McAllister and Worth 6 Reference Sztark, Payen and Piriou 8 mitochondria play a role in the pathogenesis of certain chronic non-communicable diseases (NCD). In addition, many clinical and experimental studies have demonstrated a close relationship between nutritional status during embryonic development and the occurrence of metabolic impairment in the adult brain. The close correlation between poor early nutrition and subsequent metabolic dysfunction has led investigators to speculate that early insult to the mitochondrion is a key causative factor in the eventual occurrence of disease. This review focuses in particular on evidence of neural dysfunction associated with developmental undernutrition that results in damage to mitochondrial function. To place these subjects in proper context, we will first describe to the role of the mitochondrion in reactive oxygen species (ROS) production and oxidative stress, and then explore how ROS production (mitochondrial and non-mitochondrial) and nutrition-dependent mitochondrial damage specifically contribute to the development of neurogenic disease.

Oxidative phosphorylation products: ATP and ROS

Energy production in mitochondria depends mainly upon a proton motive force generated by the electron transport chain (ETC), which transfers electrons through reduced cofactors, NADH and FADH2, derived from either the oxidation of acetyl-CoA derived from the tricarboxylic acid (TCA) cycle or β-oxidation of fatty acids to molecular oxygen (O2) as a final electron acceptor. The energy generated by the flow of electrons through the ETC is used to transport protons outward across the inner mitochondrial membrane, and the influx of those protons into the matrix through the ATP synthase complex is used to generate ATP from ADP+Pi. When the ETC becomes highly saturated with electrons, excess electrons can be directly transferred to O2 to generate the superoxide anion (O2 ), which can be further reduced to a hydroxyl radical (OH), an oxidizing agent even more damaging to cells than O2 .Reference Melov 9 In animals living in an aerobic environment, mitochondria are the major source of ROS, whose production depends essentially on O2 concentration and the electron flow velocity.Reference Turrens, Freeman, Levitt and Crapo 10 , Reference Boveris, Oshino and Chance 11 Due to fluctuations in cellular respiration, the amounts of O2 available to the ETC also fluctuate and consequently the generation of ROS can vary considerably among different tissues.Reference Turrens 12 Reference Halliwell 16

Mitochondria, on the other hand, also have a high antioxidant capacity residing in both enzymatic and non-enzymatic systems. The role of these antioxidant systems is to convert the ROS into harmless molecules, or at least into less reactive species.Reference Halliwell 17 The enzymatic antioxidant system employs an enzymatic cascade in which each enzyme uses the product from the prior reaction as a substrate for use by the next enzyme [i.e. O2 conversion to hydrogen peroxide (H2O2) by superoxide dismutase (SOD); then H2O2 to H2O by either catalase (CAT) or glutathione peroxidase (GPx)], while the non-enzymatic antioxidant system relies on molecules such as reduced glutathione (GSH) that are capable of donating H+, to stabilize the reactive species.Reference Halliwell 18 Reference Jackson, Papa and Bolanos 20 Furthermore, H2O2 and organic peroxides can be reduced by thioredoxins and peroxiredoxins that use thiol compounds (SH) as their source of electrons.Reference Conrad, Schick and Angeli 21 , Reference Perkins, Nelson, Parsonage, Poole and Karplus 22

An imbalance between ROS production and removal in favor of retention of the oxidant compounds results in a condition of oxidative stress, characterized by oxidative damage to lipids, proteins, DNA that are causal to several clinical abnormalities.Reference Hirooka 23 Reference Fisher-Wellman, Bell and Bloomer 26 In this review, we focus on altered mitochondrial ROS production and oxidative imbalance triggered by protein restriction during fetal development and its relation to the occurrence of specific neural disorders later in life.

Superoxide production sources

Superoxide, in most cases, is the first ROS produced, and it can be formed by auto-oxidizable reactions of non-radical molecules, both in mitochondrial enzymatic sites and non-mitochondrial enzymatic reactions.Reference Powers and Jackson 27

Two non-mitochondrial enzymatic reactions involve NADPH oxidase and xanthine oxidases. The first of these is a protein complex composed of membrane-associated cytochrome (b558) containing the subunits (gp91phox and p22phox), plus regulatory subunits localized in cytosol (p47phox, p40phox e p67phox) and a small G protein (Rac1 or Rac2). Although this enzyme complex is best recognized in phagocytic cells such as neutrophils, other cell types also produce O2 through NADPH oxidase activity.Reference Li and Shah 28 Xanthine oxidase also results in the non-mitochondrial production of superoxide, and is often activated following ischemia reperfusion, wherein hypoxanthine and xanthine components are oxidized to urate with concomitant O2 production.Reference Pritsos 29 For more information about those sources of ROS, see the reviews by Cantu-Medellin and Kelly and Bedard and Krause.Reference Cantu-Medellin and Kelley 30 , Reference Bedard and Krause 31

The mitochondrial monovalent reduction of O2 to O2 is thermodynamically favored and is regulated by two factors. The first is the concentration of electron carrier in proteins in a redox form and the second is the proportion of these proteins that are able to react with O2.Reference Murphy 32 Although complexes I and III are the major sources of mitochondrial ROS,Reference Turrens 13 there are additional mitochondrial sites that are able to produce ROSReference Murphy 32 Reference Quinlan, Orr and Perevoshchikova 34 (see Fig. 1). Some of these are described below:

  1. (1) Pyruvate dehydrogenase (PDH) is a mitochondrial enzymatic complex with three main catalytic componentsReference Fisher-Wellman, Gilliam and Lin 35 responsible for catalyzing the conversion of pyruvate to acetyl-CoA. It is proposed that the rate of ROS production from the PDH complex increased as the NAD(P)H/NAD(P)+ pool reduce.Reference Brautigam, Wynn, Chuang and Chuang 36 , Reference Ambrus, Nemeria and Torocsik 37

  2. (2) 2-oxoglutarate dehydrogenase is another important mitochondrial enzymatic complex present in the Krebs (TCA) cycle that is able to produce ROS through NADH oxidation.Reference Tretter and Adam-Vizi 38 The mechanism relies on a third enzymatic element, in which the flavin from dihydrolipoamide dehydrogenase can generate large amounts of ROS in the mitochondrial matrix as consequence of NADPH/NAD+ ratio.Reference Starkov, Fiskum and Chinopoulos 39

  3. (3) Mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a coenzyme located in the outer surface of the inner mitochondrial membrane that is able to transfer reduced cytosolic factors to the mitochondrial ETC.Reference Orr, Quinlan, Perevoshchikova and Brand 40 In addition to the ROS generated from mGPDH, oxidation of glycerol 3-phosphate can drive electrons both to complex IV and to complex I, leading to additional ROS production from these mitochondrial sources/sites.Reference Tretter, Takacs, Hegedus and Adam-Vizi 41

  4. (4) Electron transferring flavoprotein Q oxidoreductase (ETF-QOR). During fatty acid oxidation mitochondrial acyl-CoA dehydrogenase transfers electrons to ETF, which is then oxidized by ETF-QOR by donating electrons to the ubiquinone (UQ) pool.Reference St-Pierre, Buckingham, Roebuck and Brand 42 Once the ratio of reduced ubiquinone (UQH2) and UQ becomes elevated, the electron leak increases ROS generation.Reference Perevoshchikova, Quinlan, Orr, Gerencser and Brand 43

  5. (5) Monoamine oxidase (MAO) is a flavoenzyme located in the outer mitochondrial membrane that deaminates biogenic amines in the central and peripheral nervous systems and bloodReference Di Lisa, Kaludercic, Carpi, Menabo and Giorgio 44 , Reference Youdim, Edmondson and Tipton 45 in two-step reactions. In the first reaction, the flavin prosthetic group is reduced and produces aldehyde and ammonium. In the second, the reduced flavin is oxidized to form H2O2.Reference Tipton, Boyce, O’Sullivan, Davey and Healy 46 , Reference Toninello, Salvi, Pietrangeli and Mondovi 47

  6. (6) Flavin site in complex II. Although the estimated O2 generation by this complex is ordinarily low, in a condition of low levels of succinate and diminished activities of complexes I and III, the flavin site complex can produce both superoxide and H2O2 at high rates.Reference Turrens 13 The mechanism proposed for this is based on the electron leak achieved by flavin in the semi- or fully reduced state.Reference Quinlan, Orr and Perevoshchikova 34

  7. (7) Flavin prosthetic group in complex I. This process relies on the flavin mononucleotide (FMN) binding site, whose full reduction during forward electron flow from NADH induces electron leak to O2, producing O2 .Reference Herrero and Barja 48

  8. (8) Ubiquinone site in complex I. This source of O2 is associated with the reduction of UQ to UQH2 by a substrate such as succinate, glycerol 3-phosphate or acyl-CoA. However, the electrons can also be driven reversely from UQH2 to NAD+, thereby generating O2 at high rates.Reference Brand 33 , Reference Lambert and Brand 49

  9. (9) Outer ubiquinone site in complex III. The O2 production in this complex is based upon the electron transfer mechanism called Q cycle. Electron carriers into this complex gather the electrons from UQH2 to water-soluble cytochrome c in a sequential process that results in the formation of an unstable semiquinone UQ that can reduce O2 to superoxide.Reference Figueira, Barros and Camargo 14

Fig. 1 Schematic representation of the mitochondrial sites of reactive oxygen species (ROS) production and Ca2+-related ROS increase. In light blue, sites of ROS production: MAO, monoamine oxidase; PDH, pyruvate dehydrogenase; OGDH, oxoglutarate dehydrogenase; SDH, succinate dehydrogenase; ETF-QOR, electron transferring flavoprotein Q oxidoreductase; mGPDH, mitochondrial glycerol 3-phosphate dehydrogenase; electron transport chain complexes I and III. In gray, the proteins responsible for Ca2+ influx: RyR, ryanodine receptor; MCU, mitochondrial Ca2+ uniporter and RaM, rapid mode of calcium uptake. Dashed red lines indicate what enzymes have their ROS production stimulated by Ca2+ overload: OGDH and PDH. In light green, the proteins responsible for Ca2+ efflux: NCLX, Ca2+/Na+ exchanger and LETM1, Ca2+/H+ antiporter. Dark blue represents the other mitochondrial complexes; white ellipse; other enzymes from Krebs cycle; white rectangle, Voltage-dependent channels, VDAC; and purple, the sarcoplasmic reticulum.

Calcium (Ca2+) signaling and mitochondrial ROS overproduction

A compelling body of evidence shows that Ca2+ regulates numerous cellular functions, and that differences in Ca2+ concentration are controlled by complex membrane transport systems moving the cation between the extracellular environment, the cytosol and membrane de-limited intracellular organelles.Reference Babcock, Herrington, Goodwin, Park and Hille 50 The mitochondrion stands out as a critically important organelle in Ca2+ homeostasis as this organelle can internalize cytoplasmic calcium derived from the extracellular environment as well as Ca2+ released from the smooth endoplasmic reticulum (SER) (syn. in muscle: ‘sarcoplasmic’ reticulum) (SR).Reference Babcock, Herrington, Goodwin, Park and Hille 50 , Reference Takeuchi, Kim and Matsuoka 51

Calcium crosstalk between mitochondria and the SER employs a ryanodine receptor (RyR)-mediated mechanism. Although recent evidences have described the expression of mitochondrial inner membrane RyR in cardiomyocytes and striatal neurons,Reference Jakob, Beutner and Sharma 52 the RyR is better described as a channel protein located on the SER membrane that is sensitive to small changes in cytosolic Ca2+ concentration and to Ca2+ overload in the SER lumen.Reference Van Petegem 53 In either situation, the RyR allows Ca2+ release from storage in the SER (or SR) into the cytosolic mitochondrial microdomains that facilitate Ca2+ uptake.Reference Csordas, Varnai and Golenar 54 , Reference Csordas and Hajnoczky 55 Voltage-dependent channels located in outer mitochondrial membrane allow the entry of Ca2+ into the intermembrane space, and then either of two different processes can mediate its influx into the mitochondrial matrix:

  1. (1) The mitochondrial calcium uniporter (MCU), which relies on the negative mitochondrial membrane potential to take up Ca2+ into the matrix.Reference Takeuchi, Kim and Matsuoka 51

  2. (2) A rapid mode of calcium uptake (known as RaM), which is thought to respond to rapid changes in cytosolic Ca2+.Reference Santo-Domingo and Demaurex 56

Calcium efflux, on the other hand, depends upon the Ca2+/Na+ exchanger (NCLX), which is also able to switch the ion exchange flow (either forward or reverse) depending on cytosolic Na+ concentration and mitochondrial membrane potential.Reference Kim and Matsuoka 57 Efflux is also dependent on the Ca2+/H+ antiporter, which appears to be especially important in tissues that have low NCLX activity, such as liver, kidney and lung.Reference Saris and Carafoli 58

Several reports have shown that Ca2+ can stimulate ROS production by different mechanisms:

  1. (1) Krebs cycle stimulation. It has been proposed that Ca2+ can allosterically activate enzymes, such as PDH, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase in order to supply the ETC with reduced cofactors.Reference McCormack and Denton 59 As discussed previously some of these enzymes can also produce ROS.Reference Brand 33

  2. (2) A change in lipid organization in the inner mitochondrial membrane. Studies in model membranes suggest that Ca2+ sequesters the cardiolipin attached to membrane carrier proteins, and that this membrane rearrangement in some way increases ROS production.Reference Grijalba, Vercesi and Schreier 60

  3. (3) Mobilization of intramitochondrial ferrous iron (Fe 2+ ). Studies using isolated mitochondria have indicated that mitochondrial Ca2+ overload is associated with an increase in hydroxyl radical formation and oxidative damage. However, when the mitochondria were treated with a Fe2+ chelator, the oxidative damage was abolished.Reference Castilho, Kowaltowski, Meinicke, Bechara and Vercesi 61

  4. (4) Opening of the mitochondrial permeability transition pore (MPTP). The outer mitochondrial membrane allows essentially a ‘free’ translocation of small molecules from the cytosol into the mitochondrion. However, selective transporters in the inner mitochondrial membrane are needed to assure homeostasis between cytosolic and matrix environments.Reference Rao, Carlson and Yan 62 Mitochondrial Ca2+ overload combined with oxidative imbalance leads to the opening of the MPTP in the inner membrane, thereby allowing bidirectional traffic of small metabolites through the mitochondrial membraneReference Grancara, Battaglia and Martinis 63 and a disruption of the normal electrolytic equilibrium. This disruption leads to mitochondrial swelling, a decrease in proton motive force, an increase of ROS production, and may also rupture the outer mitochondrial membrane with the consequent release of pro-apoptotic factors (e.g. cytochrome c, Smac/DIABLO, Omi/HtrA2 and others) into the cytosol.Reference Quintanilla, Jin, von Bernhardi and Johnson 64 , Reference Frezza, Cipolat and Martins de Brito 65

Oxidative impairment in the central nervous system (CNS): the mitochondrion as a trigger of neurogenic disease

Oxidative damage is innate to all eukaryotic cells. However, tissue types vary in their sensitivity to that damage, and by that measure the brain stands out as being particularly vulnerable to oxidative damage due to its morphologic and physiologic characteristics.Reference Halliwell 16 In normal resting conditions, the adult brain is responsible for over 15% of total O2 consumption, an exceptionally large rate of oxygen use per unit mass compared with others tissues.Reference Halliwell 16 In addition to its heavy consumption of O2, the brain is also vulnerable to oxidative damage due to the specialized characteristics of neural tissue as described below:

  1. (1) The presence of excitotoxic amino acids, such as glutamate. Glutamate levels are tightly controlled in the brain, however, under conditions of stress, neurons undergoing apoptosis release a large amount of glutamate into the surrounding tissue. Furthermore, Mailly et al.Reference Mailly, Marin, Israel, Glowinski and Premont 66 showed that neurons in the presence of excess hydrogen peroxide enter a prolonged excitatory state triggered by the continuous activation of n-methyl-d-aspartate (NMDA) receptors by glutamate.

  2. (2) A high content of biologically important amines that are oxidized in the presence of O2. Neurotransmitters such as dopamine, serotonin, adrenalin and noradrenalin react slowly with oxygen to produce superoxide, which in turn reacts with those neurotransmitters to form other ROS in a chain reaction.Reference Spencer, Jeyabalan, Kichambre and Gupta 67 Furthermore, several oxygenases possess tetrahydropteridine as a co-factor, which in elevated levels is able to induce ROS-dependent neuronal apoptosis.Reference Cardaci, Filomeni, Rotilio and Ciriolo 68

  3. (3) SOD-independent H2O2 generation. Most ROS production occurs downstream from the dismutation of O2 . However, the brain can generate large quantities of H2O2 independently of SOD activity. During the recycling of biogenic amines (e.g. serotonin, epinephrine, norepinephrine, dopamine), enzymes located in outer mitochondrial membranes of neurons and glia can form H2O2 through oxidative deamination of those amines.Reference Zheng, Gal and Weiner 69 , Reference Kwan, Bergeron and Abell 70

  4. (4) Prevalence of polyunsaturated fatty acids (PUFA) in the CNS. PUFA are widespread in the CNS, and if antioxidant systems are not adequate to inhibit ROS formation, the ROS can remove hydrogen from PUFA or attach to it to initiate lipid peroxidation.Reference Shichiri 25 Once lipid peroxidation has been initiated, intermediate compounds react with oxygen to form lipid proxy radicals, which then react with PUFA in a cyclic reaction to generate isoprostanes as well as multiple α,β-unsaturated aldehyde products, such as acrolein, 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA).Reference Cobb and Cole 71

Due to the brain’s particular vulnerability to oxidative stress, many studies have been designed to assess how varying relationships among mitochondria, oxidative imbalance and lipid peroxidation can predispose an individual to neurodegenerative diseases such as Alzheimer’s (AD), Huntington’s, Parkinson’s diseases, multiple sclerosis and neurogenic hypertension.

In the case of AD, it was shown that oxidative stress as well as lipid peroxidation in the cerebral cortex and hippocampus exert a positive influence on disease progression by inducing amyloid-beta peptide (Aβ) accumulation,Reference Pratico, Uryu, Leight, Trojanoswki and Lee 72 wherein products of lipid oxidation impair energy production in the brain.Reference Reed, Pierce, Markesbery and Butterfield 73 Moreover, AD patients exhibit lower cerebral activity of mitochondrial enzymes in the Krebs cycleReference Bubber, Haroutunian, Fisch, Blass and Gibson 74 as well as an impairment in oxygen consumption via a decrease in complex I and III activities.Reference Chen, Stern and Yan 75 Such metabolic dysfunctions in neural tissue lead to an increase in ROS generation and a decrease in energy supply, thus enhancing the damage promoted by Aβ accumulationReference Chen, Stern and Yan 75 and impairing many higher level brain functions, including judgment, memory and orientation.

Similarly a dysfunction in complex II may represent an important factor in Huntington’s disease (HD), a disorder associated with cognitive deficits, psychiatric illness and involuntary movements. Striatal degeneration induced by defective mitochondrial complex II function has been used as a common animal model of HDReference Damiano, Galvan, Deglon and Brouillet 76 and may reflect the disease process in humans Furthermore, disruptions in hippocampal calcium signaling, mitochondrial membrane potential, sensitivity of the MPTP, pyruvate dehydrogenase and complex IV activities, and an increase in lipid peroxidation have also been described in brains of patients with HD.Reference Cobb and Cole 71 , Reference Nasr, Gursahani and Pang 77

Systemic inhibition of complex I has been used as an experimental model of Parkinson’s disease (PD).Reference Luo, Hoffer, Hoffer and Qi 78 Complex I disruption in dopaminergic neurons, present mainly in the striate nucleus, results in decreased ATP production and increased mitochondrial ROS production, thereby stimulating pathways involved in MPTP activation as well as initiating the release of inflammatory and pro-apoptotic molecules to induce neuronal cell death.Reference Abdin and Sarhan 79 Increased products from lipid peroxidation, such as F2-isoprostanes and 4-HNE can also contribute to neuronal deathReference Shichiri 25 , Reference Seet, Lee and Lim 80 in PD, which culminates in bradykinesia, rigidity and tremors induced by the striatal dopamine deficiency.Reference Seet, Lee and Lim 80

Mitochondrial dysfunction has also been related to neuropathology of multiple sclerosis (MS). A decrease in the complexes I and III activities of 50% or more impairs the capacity of mitochondria to produce ATP.Reference Dutta, McDonough and Yin 81 , Reference Schapira 82 The mismatch between energy requirements and ATP production in turn, contributes to axonal degeneration in upper motor neurons in MS patients.Reference Dutta, McDonough and Yin 81 , Reference Broadwater, Pandit and Clements 83 The energy deficit is further enhanced by damage to mitochondrial DNA caused by nitric oxide or its products.Reference Sarti, Giuffre and Barone 84 In amyotrophic lateral sclerosis (ALS), a neurologic disease characterized by motor neuron and neuromuscular junction degradation, oxidative stress is a major contributor to the etiology of the disease by impairing the machinery of transmitter release in the pre-synaptic motor nerve terminal of the neuromuscular junction.Reference Pollari, Goldsteins, Bart, Koistinaho and Giniatullin 85 In fact, a mutation in the gene coding for cytosolic SOD (SOD1) is responsible for 20% of ALS cases.Reference Robberecht and Philips 86 In addition, ALS patients exhibit decreased mitochondrial function and impairment in Ca2+ homeostasis, both of which contribute to oxidative damage in the lumbar and thoracic spinal cord.Reference Beal, Ferrante and Browne 87 It is proposed that the downstream oxidative damage in ALS patients depends largely on the capacity of the defective SOD1 to increase ROS production both in mitochondria and in plasma membrane bound NADPH oxidase.Reference Estevez, Crow and Sampson 88 , Reference Harraz, Marden and Zhou 89

Central redox balance also plays a key role in cardiac diseases arising from CNS defects.Reference Paravicini and Touyz 90 Nuclei located in the brainstem, including the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitaries (NTS) play key roles in neurogenic hypertension,Reference Chan and Chan 91 wherein the imbalance of ROS and nitric oxide in neurons within these nuclei can alter the peripheral vascular system by increasing sympathetic vasomotor tone.Reference Hirooka 23 , Reference Hirooka, Kishi, Sakai, Takeshita and Sunagawa 92 Chan et al. demonstrated that in spontaneously hypertensive rats, the increase in blood pressure is directly related to lower expression and activity of mitochondrial superoxide dismutase and catalase in the RVLM.Reference Chan, Tai, Li and Chan 93 Additional studies found that the elevation of O2 and H2O2 in brainstem sites such as RVLM and NTS originate from activation of NADPH oxidase via protein kinase C and phosphatidylinositol 3-kinase, as well as via an increase in intracellular Ca2+, and down regulation of mitochondrial uncoupling protein 2 (UCP2) and reduction in ETC capacityReference Chan, Wu, Chang, Tai and Chan 94 Reference Nozoe, Hirooka and Koga 97 contributes to the increase in arterial blood pressure.

Early oxidative stress as a developmental determinant of health and disease in later life

It is well known that environmental influences can alter numerous internal body functions and as a result can trigger such NCD as diabetes, metabolic syndrome, and cardiac disorders.Reference Godfrey, Gluckman and Hanson 98 An increase in NCD risk is not limited to physiologic changes occurring in adulthood but may also result from adverse events that occur much earlier in life. Thus, endogenous and exogenous signalsReference Lucas, Fewtrell and Cole 99 if occurring within certain critical developmental windows within the embryonic period can permanently affect physiologic processes within the mature individual.Reference Colombo 100

The first suggestion that this phenomenon exists came from observations of the occurrence of impaired glucose tolerance and the development non-insulin-dependent diabetes in a 64-year old who had exhibited a significantly reduced growth rate in early life.Reference Hales, Barker and Clark 101 The data suggested that poor nutrition during periods of fetal life and infancy induced diabetes via changes in B-cell function. The researchers further hypothesized that permanent adaptations to the early nutritional deficit provided survival benefits by shunting glucose to critical organs and away from those organs considered as secondary for survival.Reference Hales, Barker and Clark 101 Ironically the permanent adaptations so necessary for survival in fetal life/infancy may be the same physiologic alterations that predispose and individual to chronic disease in later life.

The ability to express different phenotypes following a physiologic challenge is known as phenotypic plasticity, and in development is dependent upon specific temporal windows during which the organism is especially prone to change its developmental pattern in order to survive.Reference Pigliucci 102 Further investigation has shown that the post-developmental environment helps to determine whether the initial exposure will or will not be harmful.Reference Khan, Dekou, Hanson, Poston and Taylor 103 , Reference Hanson and Gluckman 104 This suggested that the early influences acted as environmental cues that led to adaptive responses providing survival advantages to the individual in later life. However, if the postnatal environment does not ‘match’ or coordinate with the prenatal environment, the adaptations that occurred during development would no longer be advantageous to the individual and would predispose him or her to the occurrence of adult diseases.Reference Nettle, Frankenhuis and Rickard 105

As human mothers are able to quench small environmental perturbations of short duration,Reference Wells 106 it would be expected that environmental changes during life generate a mother’s phenotype and this phenotype will shape the offspring’s adaptations, by generating a variability in metabolic capacity.Reference Wells 107 , Reference Wells 108 WellsReference Wells 107 , suggested that the maternal phenotype is responsible for the adaptations in her offspring, and that her phenotype might depend, in turn, on the environmental history of close ancestors, as has been reviewed in detail.Reference Bale 109

Martin-Gronert and OzanneReference Martin-Gronert and Ozanne 110 highlighted three proposed mechanisms of how events in the perinatal period of development can produce life-long effects in the individual. The first mechanism involves the occurrence of permanent structural changes in key organs such as the brain, pancreas and kidney. The second mechanism involves changes in gene expression resulting from epigenetic modification, as has been described elsewhereReference Martinez, Gay and Zhang 111 , Reference Ozanne and Constancia 112 (e.g. DNA methylation, histone modification and microRNA action on mRNA).Reference Martinez, Gay and Zhang 111 The third mechanism for the long-lasting effects of a developmental insult is dependent upon the process of cellular ageing. An example of this is the induction of cellular senescence secondary to mitochondrial dysfunction and increased oxidative stress, as suggested by Luo et al.Reference Luo, Fraser and Julien 113

In the past several years, oxidative stress has been studied as a molecular trigger for the effect of maternal nutritional deficiency on NCD occurring later in life in her offspring. In animal models of protein restriction, researchers have found mitochondrial dysfunction in the early mouse embryoReference Mitchell, Schulz, Armstrong and Lane 114 and heart; oxidative stress in pancreatic islets as a consequence of a mismatch among antioxidant enzymes (i.e. increase in SOD with concomitant decrease in CAT and GPx);Reference Theys, Clippe, Bouckenooghe, Reusens and Remacle 115 an increase in pancreatic oxidative stress and heart rate associated with agingReference Tarry-Adkins, Chen, Jones, Smith and Ozanne 116 and an increase in the protein expression of enzymes related to ROS production as well as oxidative stress and DNA damage.Reference Tarry-Adkins, Martin-Gronert and Fernandez-Twinn 117

Early low-protein diet and cerebral oxidative impairment

Nutrition is often considered as the greatest exogenous influence in early life. Classified as the main non-genetic contributor to changes in brain development, nutritional inadequacy has been known to have several deleterious effects on the fetal brain.Reference McGaughy, Amaral and Rushmore 118 Reference Field, Anthony and Engle 122 Early studies of restrictive diets on offspring had described oxidative impairment, such as decreased GSH levels in the forebrain;Reference Partadiredja, Worrall and Bedi 123 lower mRNA expression of SOD and CAT in the brain;Reference Partadiredja, Worrall, Simpson and Bedi 124 increased vascular O2 productionReference Franco, Akamine and Reboucas 125 and a decrease in SOD activity,Reference Franco Mdo, Dantas and Akamine 126 and in newborn infants, an increase in oxidative damage as a consequence of the reduction in serum antioxidant capacity.Reference Gupta, Narang, Banerjee and Basu 127 , Reference Gveric-Ahmetasevic, Sunjic and Skala 128

Although all categories of nutrient are important in brain development, protein has the greatest effect on neural function.Reference Tonkiss, Galler, Morgane, Bronzino and Austin-LaFrance 129 Early protein deficiency affects the brain in several ways that vary with the period of exposure, the type of protein deficiency and its severity, and also with the specific cerebral region.Reference Morgane, Austin-LaFrance and Bronzino 130 The critical period for brain development is marked by several specific temporal windows in which the processes of neurogenesis, neuron migration, and neuron alignment and orientation are quickly increased then either decreased or ceased.Reference Morgane, Mokler and Galler 131

As proteins do not readily cross the placenta into the fetal circulation, nutritional deficits in the mother are generally transmitted to the fetus the level of the amino acid composition of the ingested protein. Consequently, the lack of any one of the essential amino acids in the maternal protein diet can lead to a complete protein deficiency in the fetus.Reference Morgane, Mokler and Galler 131 Nutritional protein restriction may reduce antioxidant capacity by inhibiting the synthesis of antioxidant enzymes,Reference Al-Gubory, Fowler and Garrel 132 and the resulting oxidative stress on fetal cells could alter gene expression and further damage the cells with oxidized proteins and lipids.Reference Luo, Fraser and Julien 113

Several studies have demonstrated the effects of protein restriction in oxidative balance and mitochondrial function in the CNS (see Fig. 2). Bonatto et al.Reference Bonatto, Polydoro and Andrades 133 evaluated these parameters in the hippocampus of rats exposed to moderate protein restriction from the 1st day of the gestational period until 75 days of postnatal life and found an increase in protein oxidation but a decrease in lipid oxidation. The investigators suggested that the opposing effects of a protein-restricted diet on proteins v. lipids resulted from an overall increase in SOD activity in the protein-restricted group, wherein the elevated SOD protected lipid, but not protein, from oxidation. As the activity of CAT did not change with restricted protein, it was suggested that the higher activity of SOD without a concomitant up-regulation of CAT drives the accumulation of H2O2, followed by formation of the hydroxyl radical (OH),Reference Halliwell 134 considered among the most reactive of ROS. Thus hydroxyl radical formation could be the responsible for the increased protein oxidation observed in the face of increased SOD activity.Reference Jackson, Schraufstatter and Hyslop 135 , Reference Gutteridge and Wilkins 136 As evidence of this, when the protein-restricted animals were supplemented with methionine, SOD activity was reduced and the animals exhibited increased oxidative damage to their lipids.

Fig. 2 Main findings on early protein restriction and central nervous system oxidative balance. Red lines represent protein restriction, blue lines, normoprotein diet, and the length of each approximates the time during which either feeding state was applied for each study referred to in the text. Numbers in parentheses refer to the references cited in the text. MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GPx, glutathione peroxidase; GST, glutathione-S-transferase; GR, glutathione reductase; G6PDH, glucose-6-phosphate dehydrogenase; GSH, reduced glutathione; GSSG, oxidized glutathione; TAR, total antioxidant reactivity; Try, tryptophan; Tyr, tyrosine; and RCR respiratory control ratio.

Further investigations in 21-day-old rats,Reference Bonatto, Polydoro and Andrades 133 , Reference Bonatto, Polydoro and Andrades 137 showed that low-protein diet increases oxidative damage to lipids in the cerebellum and hippocampus but has no influence on oxidation, in the cortex. Evaluation of SOD and CAT activities in those brain regions, moreover, showed that SOD activity was reduced only in cerebellum with low-protein diet, and not in either the cortex or hippocampus. A possible explanation for the cerebellar damage, is that low-protein induced decrease in SOD activity enhances interaction between O2 and NO to form peroxynitrite, which is capable of oxidizing lipids, proteins and thiol compounds as well as DNA.Reference Alvarez and Radi 138

Feoli et al.,Reference Feoli, Siqueira and Almeida 139 on the other hand, showed no difference in ROS production in either cerebellum, cortex or hippocampus of animals fed a low-protein diet (casein 7%) from the first gestational day until 60 days of life. Although ROS levels did not change, an increase in lipid peroxidation in the cerebellum and cortex occurred due to a decrease in SOD activity in the cerebellum, and the reduction in total antioxidant reactivity in the cortex. When the authors evaluated the content of tryptophan and tyrosine, (important neurotransmitter precursors) as a measure of damage, all three brain regions were negatively affected by low-protein diet, and the damage was closely related to the lower serotoninergic and catecholaminergic neurotransmitter concentrations.Reference Voog and Eriksson 140

Tatli et al.,Reference Tatli, Guzel and Kizil 141 by evaluating three types of induced CNS damage: (1) intrauterine growth restriction (IUGR), (2) moderate and (3) severe protein restriction in five different CNS regions (cortex, cerebellum, cervical, thoracic and lumbar cord) showed that only severe undernutrition triggered lipid oxidation in all five CNS structures at 60 days of life. Protein oxidation was shown to vary in proportion to the degree of undernutrition, with the cerebellum showing greater sensitivity to protein oxidation than the other CNS regions. In addition to increasing oxidative biomarkers, early nutritional adversity also decreased the activity of SOD and CAT in all regions analyzed.

In our laboratory, we have evaluated offspring through 100 days of age from mothers fed a low-protein diet throughout the perinatal period (gestation and lactation) and found that low-protein animals had increased oxidative damage in the brainstem. The data showed a marked decrease in antioxidant capacity, wherein enzymatic activities of SOD, CAT, GPx and glutathione-S-transferase were decreased by over 15%. The redox state was also affected by the maternal low-protein diet through a reduction in glutathione concentrations as a consequence of lower glutathione resynthesis and a decrease in NADPH supply.Reference Ferreira, Liu, Fernandes and Lagranha 142 Oxidative imbalance in certain brain regions is directly related to the occurrence of cardiovascular impairments,Reference Cardoso, Colombari and Menani 143 mainly hypertension.Reference Hirooka 23 , Reference Paravicini and Touyz 90 , Reference Chan and Chan 91 , Reference Chan and Chan 144 Thus, it is feasible that early nutritional insult is a central trigger for the development of hypertension in adulthood.

Assessing brain O2 consumption, Muzzo et al.Reference Muzzo, Gregory and Gardner 145 found that newborns from mothers fed throughout the gestational period with a diet containing only 4% protein, exhibited decreases in both brain mitochondrial protein and in O2 consumption. Animals that were reefed from the 1st until 16th postnatal day also showed a reduction in O2 consumption and phosphorylation capacity. Although the gestational period encompasses most of the period during which neurogenesis occurs,Reference Alamy and Bengelloun 146 in rats, the duration of maternal lactation represents the most important period for brain development.Reference Morgane, Mokler and Galler 131 Thus, several studies have described effects of protein restriction during other periods of brain development that may lead to lasting changes even after refeeding due to the impairment in the metabolic activity.Reference McGaughy, Amaral and Rushmore 118 , Reference Mokler, Galler and Morgane 147

In rats experiencing severe protein restriction during a period of 30 days (from the 18th to the 48th postnatal day),Reference Olorunsogo 148 brain mitochondria were shown to have alterations in Krebs cycle, isocitrate and succinate dehydrogenase, as well as in ETC enzymes, cytochrome c oxidase and ATP synthase. In addition, the mitochondrial ETC exhibited an impairment in function, such that low-protein animals were less responsive to ADP stimulation by complexes I and II substrates.

Despite the important role of the mitochondrion in several neurogenic diseases (i.e. PD, AD, ALS, etc.), very few studies have investigated the role of mitochondrial dysfunction in the central oxidative imbalance induced in protein restriction models. The antioxidant system, however, has been shown to be significantly affected by a low-protein diet, which also contributes to the disruption of mitochondrial capacity and may compromise the overall brain function.

Conclusion

In this review, we discuss the importance of mitochondrial dysfunction and oxidative stress in the development of neural disorders, and show how such diseases could be induced by nutritional insult during development. Although decreases in mitochondrial content and/or activity have been demonstrated in several studies employing nutritional manipulation either during the gestational and/or locational period, further investigations will be necessary to determine the specific mechanism causing mitochondrial dysfunction due to a protein-poor diet within a restricted developmental window. Compelling evidence has already shown that several neurogenic diseases are associated with mitochondrial disruption accompanying high-fat intake. Therefore it seems likely that a diet low in protein could also disrupt mitochondrial function sufficiently to induce neurogenic disease. Many studies to date have shown that protein restriction deeply affects central oxidative balance by decreasing antioxidant capacity. Further studies must be conducted, however, to assess the contribution of ROS generators in this oxidative disruption.

The underlying mechanisms responsible for impaired mitochondrial function in metabolic disorders induced by low-protein diet during embryonic development have not yet been elucidated. It is hoped, however, that prospective clinical investigations of mitochondrial function in healthy and diseased humans will begin to provide insight into precisely how early nutritional deficit and the occurrence of metabolic disease in adulthood are linked.

Acknowledgments

The authors are thankful to the FACEPE (Foundation to Support Science and Research from Pernambuco State – Brazil, APQ-1026.4-09/12) that provided financial fund for the laboratory.

References

1. Skulachev, VP. Membrane electricity as a convertible energy currency for the cell. Can J Biochem. 1980; 58, 161175.Google Scholar
2. Leverve, XM. Mitochondrial function and substrate availability. Crit Care Med. 2007; 35(Suppl. 9), S454S460.Google Scholar
3. Hagberg, H, Mallard, C, Rousset, CI, Thornton, C. Mitochondria: hub of injury responses in the developing brain. Lancet Neurol. 2014; 13, 217232.CrossRefGoogle ScholarPubMed
4. Yin, F, Cadenas, E. Mitochondria: the cellular hub of the dynamic coordinated network. Antioxid Redox Signal. 2015; 22, 961964.Google Scholar
5. Ernster, L, Schatz, G. Mitochondria: a historical review. J Cell Biol. 1981; 91(Pt 2), 227s255s.Google Scholar
6. Shaughnessy, DT, McAllister, K, Worth, L, et al. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect. 2014; 122, 12711278.Google Scholar
7. Porter, MH, Berdanier, CD. Oxidative phosphorylation: key to life. Diabetes Technol Ther. 2002; 4, 253254.Google Scholar
8. Sztark, F, Payen, JF, Piriou, V, et al. Cellular energy metabolism: physiologic and pathologic aspects. Ann Fr Anes Reanim. 1999; 18, 261269.Google Scholar
9. Melov, S. Mitochondrial oxidative stress. Physiologic consequences and potential for a role in aging. Ann N Y Acad Sci. 2000; 908, 219225.Google Scholar
10. Turrens, JF, Freeman, BA, Levitt, JG, Crapo, JD. The effect of hyperoxia on superoxide production by lung submitochondrial particles. Arch Biochem Biophys. 1982; 217, 401410.CrossRefGoogle ScholarPubMed
11. Boveris, A, Oshino, N, Chance, B. The cellular production of hydrogen peroxide. Biochem J. 1972; 128, 617630.Google Scholar
12. Turrens, JF. Superoxide production by the mitochondrial respiratory chain. Biosci Rep. 1997; 17, 38.Google Scholar
13. Turrens, JF. Mitochondrial formation of reactive oxygen species. J Physiol. 2003; 552(Pt 2), 335344.Google Scholar
14. Figueira, TR, Barros, MH, Camargo, AA, et al. Mitochondria as a source of reactive oxygen and nitrogen species: from molecular mechanisms to human health. Antioxid Redox Signal. 2013; 18, 20292074.Google Scholar
15. Andreyev, AY, Kushnareva, YE, Starkov, AA. Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc). 2005; 70, 200214.Google Scholar
16. Halliwell, B. Oxidative stress and neurodegeneration: where are we now? J Neurochem. 2006; 97, 16341658.Google Scholar
17. Halliwell, B. Free radicals and antioxidants: a personal view. Nutr Rev. 1994; 52(Pt 1), 253265.Google Scholar
18. Halliwell, B. Free radicals and antioxidants: updating a personal view. Nutr Rev. 2012; 70, 257265.CrossRefGoogle ScholarPubMed
19. Flora, SJ. Role of free radicals and antioxidants in health and disease. Cell Mol Biol (Noisy-le-grand). 2007; 53, 12.Google Scholar
20. Jackson, MJ, Papa, S, Bolanos, J, et al. Antioxidants, reactive oxygen and nitrogen species, gene induction and mitochondrial function. Mol Aspects Med. 2002; 23, 209285.Google Scholar
21. Conrad, M, Schick, J, Angeli, JP. Glutathione and thioredoxin dependent systems in neurodegenerative disease: what can be learned from reverse genetics in mice. Neurochem Int. 2013; 62, 738749.Google Scholar
22. Perkins, A, Nelson, KJ, Parsonage, D, Poole, LB, Karplus, PA. Peroxiredoxins: guardians against oxidative stress and modulators of peroxide signaling. Trends Biochem Sci. 2015; 40, 435445.Google Scholar
23. Hirooka, Y. Role of reactive oxygen species in brainstem in neural mechanisms of hypertension. Auton Neurosci. 2008; 142, 2024.Google Scholar
24. Peterson, JR, Sharma, RV, Davisson, RL. Reactive oxygen species in the neuropathogenesis of hypertension. Curr Hypertens Rep. 2006; 8, 232241.CrossRefGoogle ScholarPubMed
25. Shichiri, M. The role of lipid peroxidation in neurological disorders. J Clin Biochem Nutr. 2014; 54, 151160.CrossRefGoogle ScholarPubMed
26. Fisher-Wellman, K, Bell, HK, Bloomer, RJ. Oxidative stress and antioxidant defense mechanisms linked to exercise during cardiopulmonary and metabolic disorders. Oxid Med Cell Longev. 2009; 2, 4351.Google Scholar
27. Powers, SK, Jackson, MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev. 2008; 88, 12431276.Google Scholar
28. Li, JM, Shah, AM. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol. 2004; 287, R1014R1030.Google Scholar
29. Pritsos, CA. Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system. Chem Biol Interact. 2000; 129, 195208.Google Scholar
30. Cantu-Medellin, N, Kelley, EE. Xanthine oxidoreductase-catalyzed reactive species generation: a process in critical need of reevaluation. Redox biology. 2013; 1, 353358.Google Scholar
31. Bedard, K, Krause, KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007; 87, 245313.Google Scholar
32. Murphy, MP. How mitochondria produce reactive oxygen species. Biochem J. 2009; 417, 113.Google Scholar
33. Brand, MD. The sites and topology of mitochondrial superoxide production. Exp Gerontol. 2010; 45, 466472.CrossRefGoogle ScholarPubMed
34. Quinlan, CL, Orr, AL, Perevoshchikova, IV, et al. Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem. 2012; 287, 2725527264.Google Scholar
35. Fisher-Wellman, KH, Gilliam, LA, Lin, CT, et al. Mitochondrial glutathione depletion reveals a novel role for the pyruvate dehydrogenase complex as a key H2O2-emitting source under conditions of nutrient overload. Free Radic Biol Med. 2013; 65, 12011208.Google Scholar
36. Brautigam, CA, Wynn, RM, Chuang, JL, Chuang, DT. Subunit and catalytic component stoichiometries of an in vitro reconstituted human pyruvate dehydrogenase complex. J Biol Chem. 2009; 284, 1308613098.Google Scholar
37. Ambrus, A, Nemeria, NS, Torocsik, B, et al. Formation of reactive oxygen species by human and bacterial pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes reconstituted from recombinant components. Free Radic Biol Med. 2015; 89, 642650.CrossRefGoogle ScholarPubMed
38. Tretter, L, Adam-Vizi, V. Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase. J Neurosci. 2004; 24, 77717778.Google Scholar
39. Starkov, AA, Fiskum, G, Chinopoulos, C, et al. Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci. 2004; 24, 77797788.Google Scholar
40. Orr, AL, Quinlan, CL, Perevoshchikova, IV, Brand, MD. A refined analysis of superoxide production by mitochondrial sn-glycerol 3-phosphate dehydrogenase. J Biol Chem. 2012; 287, 4292142935.Google Scholar
41. Tretter, L, Takacs, K, Hegedus, V, Adam-Vizi, V. Characteristics of alpha-glycerophosphate-evoked H2O2 generation in brain mitochondria. J Neurochem. 2007; 100, 650663.Google Scholar
42. St-Pierre, J, Buckingham, JA, Roebuck, SJ, Brand, MD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem. 2002; 277, 4478444790.Google Scholar
43. Perevoshchikova, IV, Quinlan, CL, Orr, AL, Gerencser, AA, Brand, MD. Sites of superoxide and hydrogen peroxide production during fatty acid oxidation in rat skeletal muscle mitochondria. Free Radic Biol Med. 2013; 61, 298309.Google Scholar
44. Di Lisa, F, Kaludercic, N, Carpi, A, Menabo, R, Giorgio, M. Mitochondria and vascular pathology. Pharmacol Rep. 2009; 61, 123130.Google Scholar
45. Youdim, MB, Edmondson, D, Tipton, KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci. 2006; 7, 295309.CrossRefGoogle ScholarPubMed
46. Tipton, KF, Boyce, S, O’Sullivan, J, Davey, GP, Healy, J. Monoamine oxidases: certainties and uncertainties. Curr Med Chem. 2004; 11, 19651982.Google Scholar
47. Toninello, A, Salvi, M, Pietrangeli, P, Mondovi, B. Biogenic amines and apoptosis: minireview article. Amino Acids. 2004; 26, 339343.Google Scholar
48. Herrero, A, Barja, G. Localization of the site of oxygen radical generation inside the complex I of heart and nonsynaptic brain mammalian mitochondria. J Bioenerg Biomembr. 2000; 32, 609615.Google Scholar
49. Lambert, AJ, Brand, MD. Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. Biochem J. 2004; 382(Pt 2), 511517.CrossRefGoogle Scholar
50. Babcock, DF, Herrington, J, Goodwin, PC, Park, YB, Hille, B. Mitochondrial participation in the intracellular Ca2+ network. J Cell Biol. 1997; 136, 833844.Google Scholar
51. Takeuchi, A, Kim, B, Matsuoka, S. The destiny of Ca(2+) released by mitochondria. J Physiol Sci. 2015; 65, 1124.Google Scholar
52. Jakob, R, Beutner, G, Sharma, VK, et al. Molecular and functional identification of a mitochondrial ryanodine receptor in neurons. Neurosci Lett. 2014; 575, 712.Google Scholar
53. Van Petegem, F. Ryanodine receptors: structure and function. J Biol Chem. 2012; 287, 3162431632.Google Scholar
54. Csordas, G, Varnai, P, Golenar, T, et al. Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell. 2010; 39, 121132.Google Scholar
55. Csordas, G, Hajnoczky, G. SR/ER-mitochondrial local communication: calcium and ROS. Biochim Biophys Acta. 2009; 1787, 13521362.Google Scholar
56. Santo-Domingo, J, Demaurex, N. Calcium uptake mechanisms of mitochondria. Biochim Biophys Acta. 2010; 1797, 907912.CrossRefGoogle ScholarPubMed
57. Kim, B, Matsuoka, S. Cytoplasmic Na+-dependent modulation of mitochondrial Ca2+ via electrogenic mitochondrial Na+-Ca2+ exchange. J Physiol. 2008; 586, 16831697.Google Scholar
58. Saris, NE, Carafoli, E. A historical review of cellular calcium handling, with emphasis on mitochondria. Biochemistry (Mosc). 2005; 70, 187194.Google Scholar
59. McCormack, JG, Denton, RM. Mitochondrial Ca2+ transport and the role of intramitochondrial Ca2+ in the regulation of energy metabolism. Dev Neurosci. 1993; 15, 165173.Google Scholar
60. Grijalba, MT, Vercesi, AE, Schreier, S. Ca2+-induced increased lipid packing and domain formation in submitochondrial particles. A possible early step in the mechanism of Ca2+-stimulated generation of reactive oxygen species by the respiratory chain. Biochemistry. 1999; 38, 1327913287.Google Scholar
61. Castilho, RF, Kowaltowski, AJ, Meinicke, AR, Bechara, EJ, Vercesi, AE. Permeabilization of the inner mitochondrial membrane by Ca2+ ions is stimulated by t-butyl hydroperoxide and mediated by reactive oxygen species generated by mitochondria. Free Radic Biol Med. 1995; 18, 479486.Google Scholar
62. Rao, VK, Carlson, EA, Yan, SS. Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. Biochim Biophys Acta. 2014; 1842, 12671272.CrossRefGoogle ScholarPubMed
63. Grancara, S, Battaglia, V, Martinis, P, et al. Mitochondrial oxidative stress induced by Ca2+ and monoamines: different behaviour of liver and brain mitochondria in undergoing permeability transition. Amino Acids. 2012; 42, 751759.Google Scholar
64. Quintanilla, RA, Jin, YN, von Bernhardi, R, Johnson, GV. Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease. Mol Neurodegener. 2013; 8, 45.Google Scholar
65. Frezza, C, Cipolat, S, Martins de Brito, O, et al. OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell. 2006; 126, 177189.Google Scholar
66. Mailly, F, Marin, P, Israel, M, Glowinski, J, Premont, J. Increase in external glutamate and NMDA receptor activation contribute to H2O2-induced neuronal apoptosis. J Neurochem. 1999; 73, 11811188.Google Scholar
67. Spencer, WA, Jeyabalan, J, Kichambre, S, Gupta, RC. Oxidatively generated DNA damage after Cu(II) catalysis of dopamine and related catecholamine neurotransmitters and neurotoxins: Role of reactive oxygen species. Free Radic Biol Med. 2011; 50, 139147.Google Scholar
68. Cardaci, S, Filomeni, G, Rotilio, G, Ciriolo, MR. p38(MAPK)/p53 signalling axis mediates neuronal apoptosis in response to tetrahydrobiopterin-induced oxidative stress and glucose uptake inhibition: implication for neurodegeneration. Biochem J. 2010; 430, 439451.Google Scholar
69. Zheng, H, Gal, S, Weiner, LM, et al. Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition. J Neurochem. 2005; 95, 6878.Google Scholar
70. Kwan, SW, Bergeron, JM, Abell, CW. Molecular properties of monoamine oxidases A and B. Psychopharmacology (Berl). 1992; 106(Suppl), S1S5.CrossRefGoogle ScholarPubMed
71. Cobb, CA, Cole, MP. Oxidative and nitrative stress in neurodegeneration. Neurobiol Dis. 2015; 84, 421.Google Scholar
72. Pratico, D, Uryu, K, Leight, S, Trojanoswki, JQ, Lee, VM. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci. 2001; 21, 41834187.Google Scholar
73. Reed, TT, Pierce, WM, Markesbery, WR, Butterfield, DA. Proteomic identification of HNE-bound proteins in early Alzheimer disease: insights into the role of lipid peroxidation in the progression of AD. Brain Res. 2009; 1274, 6676.Google Scholar
74. Bubber, P, Haroutunian, V, Fisch, G, Blass, JP, Gibson, GE. Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol. 2005; 57, 695703.Google Scholar
75. Chen, X, Stern, D, Yan, SD. Mitochondrial dysfunction and Alzheimer’s disease. Curr Alzheimer Res. 2006; 3, 515520.Google Scholar
76. Damiano, M, Galvan, L, Deglon, N, Brouillet, E. Mitochondria in Huntington’s disease. Biochim Biophys Acta. 2010; 1802, 5261.Google Scholar
77. Nasr, P, Gursahani, HI, Pang, Z, et al. Influence of cytosolic and mitochondrial Ca2+, ATP, mitochondrial membrane potential, and calpain activity on the mechanism of neuron death induced by 3-nitropropionic acid. Neurochem Int. 2003; 43, 8999.Google Scholar
78. Luo, Y, Hoffer, A, Hoffer, B, Qi, X. Mitochondria: a therapeutic target for Parkinson’s disease? Int J Mol Sci. 2015; 16, 2070420730.Google Scholar
79. Abdin, AA, Sarhan, NI. Intervention of mitochondrial dysfunction-oxidative stress-dependent apoptosis as a possible neuroprotective mechanism of alpha-lipoic acid against rotenone-induced parkinsonism and L-dopa toxicity. Neurosci Res. 2011; 71, 387395.Google Scholar
80. Seet, RC, Lee, CY, Lim, EC, et al. Oxidative damage in Parkinson disease: measurement using accurate biomarkers. Free Radic Biol Med. 2010; 48, 560566.Google Scholar
81. Dutta, R, McDonough, J, Yin, X, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol. 2006; 59, 478489.Google Scholar
82. Schapira, AH. Complex I: inhibitors, inhibition and neurodegeneration. Exp Neurol. 2010; 224, 331335.Google Scholar
83. Broadwater, L, Pandit, A, Clements, R, et al. Analysis of the mitochondrial proteome in multiple sclerosis cortex. Biochim Biophys Acta. 2011; 1812, 630641.Google Scholar
84. Sarti, P, Giuffre, A, Barone, MC, et al. Nitric oxide and cytochrome oxidase: reaction mechanisms from the enzyme to the cell. Free Radic Biol Med. 2003; 34, 509520.Google Scholar
85. Pollari, E, Goldsteins, G, Bart, G, Koistinaho, J, Giniatullin, R. The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis. Front Cell Neurosci. 2014; 8, 131.Google Scholar
86. Robberecht, W, Philips, T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci. 2013; 14, 248264.Google Scholar
87. Beal, MF, Ferrante, RJ, Browne, SE, et al. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol. 1997; 42, 644654.Google Scholar
88. Estevez, AG, Crow, JP, Sampson, JB, et al. Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science. 1999; 286, 24982500.Google Scholar
89. Harraz, MM, Marden, JJ, Zhou, W, et al. SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J Clin Invest. 2008; 118, 659670.Google Scholar
90. Paravicini, TM, Touyz, RM. Redox signaling in hypertension. Cardiovasc Res. 2006; 71, 247258.Google Scholar
91. Chan, SH, Chan, JY. Brain stem NOS and ROS in neural mechanisms of hypertension. Antioxid Redox Signal. 2013; 20, 146163.Google Scholar
92. Hirooka, Y, Kishi, T, Sakai, K, Takeshita, A, Sunagawa, K. Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension. Am J Physiol Regul Integr Comp Physiol. 2011; 300, R818R826.Google Scholar
93. Chan, SH, Tai, MH, Li, CY, Chan, JY. Reduction in molecular synthesis or enzyme activity of superoxide dismutases and catalase contributes to oxidative stress and neurogenic hypertension in spontaneously hypertensive rats. Free Radic Biol Med. 2006; 40, 20282039.Google Scholar
94. Chan, SH, Wu, KL, Chang, AY, Tai, MH, Chan, JY. Oxidative impairment of mitochondrial electron transport chain complexes in rostral ventrolateral medulla contributes to neurogenic hypertension. Hypertension. 2009; 53, 217227.Google Scholar
95. Chan, SH, Wu, CA, Wu, KL, et al. Transcriptional upregulation of mitochondrial uncoupling protein 2 protects against oxidative stress-associated neurogenic hypertension. Circ Res. 2009; 105, 886896.Google Scholar
96. Chan, SH, Chan, JY. Angiotensin-generated reactive oxygen species in brain and pathogenesis of cardiovascular diseases. Antioxid Redox Signal. 2013; 19, 10741084.Google Scholar
97. Nozoe, M, Hirooka, Y, Koga, Y, et al. Inhibition of Rac1-derived reactive oxygen species in nucleus tractus solitarius decreases blood pressure and heart rate in stroke-prone spontaneously hypertensive rats. Hypertension. 2007; 50, 6268.CrossRefGoogle ScholarPubMed
98. Godfrey, KM, Gluckman, PD, Hanson, MA. Developmental origins of metabolic disease: life course and intergenerational perspectives. Trends Endocrinol Metab. 2010; 21, 199205.CrossRefGoogle ScholarPubMed
99. Lucas, A, Fewtrell, MS, Cole, TJ. Fetal origins of adult disease-the hypothesis revisited. BMJ. 1999; 319, 245249.Google Scholar
100. Colombo, J. The critical period concept: research, methodology, and theoretical issues. Psychol Bull. 1982; 91, 260275.CrossRefGoogle ScholarPubMed
101. Hales, CN, Barker, DJ, Clark, PM, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ. 1991; 303, 10191022.CrossRefGoogle ScholarPubMed
102. Pigliucci, M. Developmental phenotypic plasticity: where internal programming meets the external environment. Curr Opin Plant Biol. 1998; 1, 8791.CrossRefGoogle ScholarPubMed
103. Khan, I, Dekou, V, Hanson, M, Poston, L, Taylor, P. Predictive adaptive responses to maternal high-fat diet prevent endothelial dysfunction but not hypertension in adult rat offspring. Circulation. 2004; 110, 10971102.Google Scholar
104. Hanson, M, Gluckman, P. Endothelial dysfunction and cardiovascular disease: the role of predictive adaptive responses. Heart. 2005; 91, 864866.Google Scholar
105. Nettle, D, Frankenhuis, WE, Rickard, IJ. The evolution of predictive adaptive responses in human life history. Proc Biol Sci. 2013; 280, 20131343.Google Scholar
106. Wells, JC. The thrifty phenotype hypothesis: thrifty offspring or thrifty mother? J Theor Biol. 2003; 221, 143161.Google Scholar
107. Wells, JC. Flaws in the theory of predictive adaptive responses. Trends Endocrinol Metab. 2007; 18, 331337.Google Scholar
108. Wells, JC. The thrifty phenotype: an adaptation in growth or metabolism? Am J Hum Biol. 2011; 23, 6575.Google Scholar
109. Bale, TL. Epigenetic and transgenerational reprogramming of brain development. Nat Rev Neurosci. 2015; 16, 332344.Google Scholar
110. Martin-Gronert, MS, Ozanne, SE. Mechanisms underlying the developmental origins of disease. Rev Endocr Metab Disord. 2012; 13, 8592.Google Scholar
111. Martinez, SR, Gay, MS, Zhang, L. Epigenetic mechanisms in heart development and disease. Drug Discov Today. 2015; 20, 799811.Google Scholar
112. Ozanne, SE, Constancia, M. Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. Nat Clin Pract Endocrinol Metab. 2007; 3, 539546.Google Scholar
113. Luo, ZC, Fraser, WD, Julien, P, et al. Tracing the origins of ‘fetal origins’ of adult diseases: programming by oxidative stress? Med Hypotheses. 2006; 66, 3844.Google Scholar
114. Mitchell, M, Schulz, SL, Armstrong, DT, Lane, M. Metabolic and mitochondrial dysfunction in early mouse embryos following maternal dietary protein intervention. Biol Reprod. 2009; 80, 622630.Google Scholar
115. Theys, N, Clippe, A, Bouckenooghe, T, Reusens, B, Remacle, C. Early low protein diet aggravates unbalance between antioxidant enzymes leading to islet dysfunction. PLoS One. 2009; 4, e6110.Google Scholar
116. Tarry-Adkins, JL, Chen, JH, Jones, RH, Smith, NH, Ozanne, SE. Poor maternal nutrition leads to alterations in oxidative stress, antioxidant defense capacity, and markers of fibrosis in rat islets: potential underlying mechanisms for development of the diabetic phenotype in later life. FASEB J. 2010; 24, 27622771.Google Scholar
117. Tarry-Adkins, JL, Martin-Gronert, MS, Fernandez-Twinn, DS, et al. Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart. FASEB J. 2013; 27, 379390.Google Scholar
118. McGaughy, JA, Amaral, AC, Rushmore, RJ, et al. Prenatal malnutrition leads to deficits in attentional set shifting and decreases metabolic activity in prefrontal subregions that control executive function. Dev Neurosci. 2014; 36, 532541.Google Scholar
119. Duran, P, Galler, JR, Cintra, L, Tonkiss, J. Prenatal malnutrition and sleep states in adult rats: effects of restraint stress. Physiol Behav. 2006; 89, 156163.Google Scholar
120. Faa, G, Marcialis, MA, Ravarino, A, et al. Fetal programming of the human brain: is there a link with insurgence of neurodegenerative disorders in adulthood? Curr Med Chem. 2014; 21, 38543876.Google Scholar
121. Airey, CJ, Smith, PJ, Restall, K, et al. Maternal undernutrition affects neurogenesis in the foetal mouse brain. Int J Dev Neurosci. 2015; 47(Pt A), 72.Google Scholar
122. Field, ME, Anthony, RV, Engle, TE, et al. Duration of maternal undernutrition differentially alters fetal growth and hormone concentrations. Domest Anim Endocrinol. 2015; 51, 17.Google Scholar
123. Partadiredja, G, Worrall, S, Bedi, KS. Early life undernutrition alters the level of reduced glutathione but not the activity levels of reactive oxygen species enzymes or lipid peroxidation in the mouse forebrain. Brain Res. 2009; 1285, 2229.Google Scholar
124. Partadiredja, G, Worrall, S, Simpson, R, Bedi, KS. Pre-weaning undernutrition alters the expression levels of reactive oxygen species enzymes but not their activity levels or lipid peroxidation in the rat brain. Brain Res. 2008; 1222, 6978.CrossRefGoogle ScholarPubMed
125. Franco, MC, Akamine, EH, Reboucas, N, et al. Long-term effects of intrauterine malnutrition on vascular function in female offspring: implications of oxidative stress. Life Sci. 2007; 80, 709715.Google Scholar
126. Franco Mdo, C, Dantas, AP, Akamine, EH, et al. Enhanced oxidative stress as a potential mechanism underlying the programming of hypertension in utero. J Cardiovasc Pharmacol. 2002; 40, 501509.Google Scholar
127. Gupta, P, Narang, M, Banerjee, BD, Basu, S. Oxidative stress in term small for gestational age neonates born to undernourished mothers: a case control study. BMC Pediatr. 2004; 4, 14.Google Scholar
128. Gveric-Ahmetasevic, S, Sunjic, SB, Skala, H, et al. Oxidative stress in small-for-gestational age (SGA) term newborns and their mothers. Free Radic Res. 2009; 43, 376384.Google Scholar
129. Tonkiss, J, Galler, J, Morgane, PJ, Bronzino, JD, Austin-LaFrance, RJ. Prenatal protein malnutrition and postnatal brain function. Ann N Y Acad Sci. 1993; 678, 215227.Google Scholar
130. Morgane, PJ, Austin-LaFrance, R, Bronzino, J, et al. Prenatal malnutrition and development of the brain. Neurosci Biobehav Rev. 1993; 17, 91128.Google Scholar
131. Morgane, PJ, Mokler, DJ, Galler, JR. Effects of prenatal protein malnutrition on the hippocampal formation. Neurosci Biobehav Rev. 2002; 26, 471483.Google Scholar
132. Al-Gubory, KH, Fowler, PA, Garrel, C. The roles of cellular reactive oxygen species, oxidative stress and antioxidants in pregnancy outcomes. Int J Biochem Cell Biol. 2010; 42, 16341650.Google Scholar
133. Bonatto, F, Polydoro, M, Andrades, ME, et al. Effect of protein malnutrition on redox state of the hippocampus of rat. Brain Res. 2005; 1042, 1722.Google Scholar
134. Halliwell, B. Free radicals, reactive oxygen species and human disease: a critical evaluation with special reference to atherosclerosis. Br J Exp Pathol. 1989; 70, 737757.Google Scholar
135. Jackson, JH, Schraufstatter, IU, Hyslop, PA, et al. Role of hydroxyl radical in DNA damage. Transactions of the Association of American Physicians. 1987; 100, 147157.Google Scholar
136. Gutteridge, JM, Wilkins, S. Copper salt-dependent hydroxyl radical formation. Damage to proteins acting as antioxidants. Biochim Biophys Acta. 1983; 759, 3841.Google Scholar
137. Bonatto, F, Polydoro, M, Andrades, ME, et al. Effects of maternal protein malnutrition on oxidative markers in the young rat cortex and cerebellum. Neurosci Lett. 2006; 406, 281284.Google Scholar
138. Alvarez, B, Radi, R. Peroxynitrite reactivity with amino acids and proteins. Amino Acids. 2003; 25, 295311.CrossRefGoogle ScholarPubMed
139. Feoli, AM, Siqueira, IR, Almeida, L, et al. Effects of protein malnutrition on oxidative status in rat brain. Nutrition. 2006; 22, 160165.Google Scholar
140. Voog, L, Eriksson, T. Toluene-induced decrease in rat plasma concentrations of tyrosine and tryptophan. Acta Pharmacol Toxicol. 1984; 54, 151153.Google Scholar
141. Tatli, M, Guzel, A, Kizil, G, et al. Comparison of the effects of maternal protein malnutrition and intrauterine growth restriction on redox state of central nervous system in offspring rats. Brain Res. 2007; 1156, 2130.Google Scholar
142. Ferreira, DJ, Liu, Y, Fernandes, MP, Lagranha, CJ. Perinatal low-protein diet alters brainstem antioxidant metabolism in adult offspring. Nutr Neurosci. 2015; doi:10.1179/1476830515Y.0000000030, in press.Google ScholarPubMed
143. Cardoso, LM, Colombari, DS, Menani, JV, et al. Cardiovascular responses to hydrogen peroxide into the nucleus tractus solitarius. Am J Physiol Regul Integr Comp Physiol. 2009; 297, R462R469.Google Scholar
144. Chan, SH, Chan, JY. Brain stem oxidative stress and its associated signaling in the regulation of sympathetic vasomotor tone. J Appl Physiol (1985). 2012; 113, 19211928.Google Scholar
145. Muzzo, S, Gregory, T, Gardner, LI. Oxygen consumption by brain mitochondria of rats malnourished in utero. J Nutr. 1973; 103, 314317.Google Scholar
146. Alamy, M, Bengelloun, WA. Malnutrition and brain development: an analysis of the effects of inadequate diet during different stages of life in rat. Neurosci Biobehav Rev. 2012; 36, 14631480.Google Scholar
147. Mokler, DJ, Galler, JR, Morgane, PJ. Modulation of 5-HT release in the hippocampus of 30-day-old rats exposed in utero to protein malnutrition. Brain Res Dev Brain Res. 2003; 142, 203208.Google Scholar
148. Olorunsogo, OO. Changes in brain mitochondrial bioenergetics in protein-deficient rats. Br J Exp Pathol. 1989; 70, 607619.Google Scholar
Figure 0

Fig. 1 Schematic representation of the mitochondrial sites of reactive oxygen species (ROS) production and Ca2+-related ROS increase. In light blue, sites of ROS production: MAO, monoamine oxidase; PDH, pyruvate dehydrogenase; OGDH, oxoglutarate dehydrogenase; SDH, succinate dehydrogenase; ETF-QOR, electron transferring flavoprotein Q oxidoreductase; mGPDH, mitochondrial glycerol 3-phosphate dehydrogenase; electron transport chain complexes I and III. In gray, the proteins responsible for Ca2+ influx: RyR, ryanodine receptor; MCU, mitochondrial Ca2+ uniporter and RaM, rapid mode of calcium uptake. Dashed red lines indicate what enzymes have their ROS production stimulated by Ca2+ overload: OGDH and PDH. In light green, the proteins responsible for Ca2+ efflux: NCLX, Ca2+/Na+ exchanger and LETM1, Ca2+/H+ antiporter. Dark blue represents the other mitochondrial complexes; white ellipse; other enzymes from Krebs cycle; white rectangle, Voltage-dependent channels, VDAC; and purple, the sarcoplasmic reticulum.

Figure 1

Fig. 2 Main findings on early protein restriction and central nervous system oxidative balance. Red lines represent protein restriction, blue lines, normoprotein diet, and the length of each approximates the time during which either feeding state was applied for each study referred to in the text. Numbers in parentheses refer to the references cited in the text. MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GPx, glutathione peroxidase; GST, glutathione-S-transferase; GR, glutathione reductase; G6PDH, glucose-6-phosphate dehydrogenase; GSH, reduced glutathione; GSSG, oxidized glutathione; TAR, total antioxidant reactivity; Try, tryptophan; Tyr, tyrosine; and RCR respiratory control ratio.