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Mini-Reviews in Medicinal Chemistry, 2015, 15, 000-000

1

Mitochondrial Dysfunction and Its Relationship with mTOR Signaling andOxidative Damage in Autism Spectrum Disorders
Kunio Yui1,*, Atsushi Sato2,3 and George Imataka4
1

Research Institute of Pervasive Developmental Disorders, Ashiya University Graduate School of
Education, Ashiya 659-8511, Japan; 2Addictive Substance Project, Tokyo Metropolitan Institute ofMedical Science, Tokyo, Japan; 3Tokyo Metropolitan Neurological Hospital, Tokyo, Japan;
4
Department of Pediatrics, Dokkyo Medical University School of Medicine, 880, Kitakobayashi, Mibu,
321-0293, Tochigi, Japan
Abstract: Mitochondria are organelles that play a central role in processes related to cellular viability,
such as energy production, cell growth, cell death via apoptosis, and metabolism of reactive oxygen
species (ROS). We can observe behavioral abnormalities relevant to autism spectrum disorders(ASDs) and their recovery mediated by the mTOR inhibitor rapamycin in mouse models. In Tsc2+/mice, the transcription of multiple genes involved in mTOR signaling is enhanced, suggesting a crucial role ofdysregulated mTOR signaling in the ASD model. This review proposes that the mTOR inhibitor may be useful for thepharmacological treatment of ASD. This review offers novel insights into mitochondrial dysfunction and the related
impaired glutathione synthesis and lower detoxification capacity. Firstly, children with ASD and concomitantmitochondrial dysfunction have been reported to manifest clinical symptoms similar to those of mitochondrial disorders,and it therefore shows that the clinical manifestations of ASD with a concomitant diagnosis of mitochondrial dysfunction
are likely due to these mitochondrial disorders. Secondly, the adenosine triphosphate (ATP) production/oxygen
consumption pathway may be a potential candidate for preventing mitochondrial dysfunction due to oxidative stress, anddisruption of ATP synthesis alone may be related to impaired glutathione synthesis. Finally, a decrease in total antioxidant
capacity may account for ASD children who show core social and behavioral impairments without neurological andsomatic symptoms.

Keywords: Adenosine triphosphate, autism spectrum disorders, impaired glutathione synthesis, mTOR signaling, oxidative
stress, rapamycin, tuberous sclerosis complex, mitochondrial dysfunction.
1. INTRODUCTION
Mitochondria are organelles that play a central role inprocesses related to cellular viability, such as energy
production, cell growth, cell death via apoptosis, andmetabolism of reactive oxygen species (ROS). A diverse
number of human diseases, ranging from diabetes mellitus toneurodegenerative disorders, stem from and commonly
coexist with mitochondrial dysfunction (MD) [1, 2].
Mutations in genes related to mitochondrial biogenesis affectmultiple organs, particularly the brain and muscles, due totheir high energy demands. These conditions are therefore
known as “mitochondrial disorders” or “mitochondrial
encephalomyopathies”, including MELAS (mitochondrial
myopathy, encephalopathy, lactic acidosis and stroke-like
episodes) [3] and MERRF (myoclonic epilepsy associatedwith ragged-red fibers [4]. Neurodegenerative disorders suchas Alzheimer’s disease, Parkinson’s disease [5], and autism
spectrum disorders (ASD) [6] are also closely related to MD*Address correspondence to this author at the Research Institute ofPervasive Developmental Disorders, Ashiya University Graduate School of
Education, Ashiya 659-8511, Japan; Tel: +81 797-23-061; Fax: +81 79723-1901; E-mail: yui16@bell.ocn.ne.jp1389-5575/15 $58.00+.00

with respect to disease occurrence and progression. In the
Diagnostic Manual of Mental Disorders, Fifth Edition(DSM-5), ASD is defined as a set of heterogeneous
neurodevelopmental conditions, characterized by early-onset
difficulties in social communication and unusually restricted
and repetitive behaviors and interests [7]. MD has been
observed among a subgroup of ASD patients exhibiting
elevated levels of lactate in their plasma and brain [6, 8, 9],as well as vulnerability to pro-oxidant micro environmental
toxicants [9].
Some mitochondrial functions, such as oxygen
consumption, adenosine triphosphate (ATP) production,
fatty acid oxidation and gene transcription, are also regulatedby mTOR [10, 11]. Impaired mitochondrial function isobserved in association with ASD-related behavioral
aberrations in mice that show mTOR activation [12]. In
addition to excessive protein synthesis [14] and alteredautophagy [15] related to neuronal alteration, MD may linkdysregulated mTOR activity to ASD.
Converging lines of research have implicated the
involvement of intracellular oxidative damage inmitochondrial diseases, a group of disorders caused by MD.
Glutathione (L-γ-glutamyl-L-cysteinylglycine, GSH) plays a© 2015 Bentham Science Publishers

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Yui et al.

key role in the cellular defense against oxidant damage [16].
Glutathione deficiency has also been reported in MD [16].
The oxidative stress-related pathophysiology of ASD
includes MD and impairment of the GSH synthesis pathway.
In view of the fact that synthesized ATP inhibits MD [17],ATP may play a crucial role in the generation of ROS to
impair GSH synthesis, resulting in a low detoxifying
capacity and MD. A low detoxifying capacity, as indicatedby a low urinary total antioxidant capacity, has been reported
in ASD children without any of the neurological and somatic
symptoms observed in children with MD or impaired
glutathione synthesis.

biosynthesis (Fig. 1). Thirdly, there is growing evidence that
intracellular oxidative damage associated with thepathophysiology of ASD appears to include MD, impaired
glutathione synthesis, or a low detoxifying capacity, but therelationship among these processes in ASD has never been
elucidated. This review also summarizes the clinicalmanifestations of ASD with MD as well as recent data on theregulation and role of biomarkers in MD, impaired
glutathione synthesis, or a low detoxifying capacity.

The relationship among MD, impaired GSH synthesis
and a low detoxifying capacity has yet to be elucidated. This
review addresses recent advances in mitochondrial function
in relation to mTOR. Moreover, this review attempts tountangle three aspects of the relationship of MD, impaired
GSH biosynthesis and a low detoxifying capacity withoxidative stress. Firstly, we discuss whether children with
ASD might have a certain subset of MD or a new type of
MD. Secondly, we attempt to shed light on potential
processes that may result from the production of ROS in two
metabolic pathways, including MD and impaired GSH

MD may be involved in ASD. As a neurodevelopmental
disorder, ASD primarily affects reciprocal social interactions
and is accompanied by restrictive, repetitive behaviors andinterests according to the DSM-5 [7]. Like most psychiatricdisorders, both genetic and environmental factors caninfluence the occurrence of ASD. Genetic research hasprovided an extensive list of genes, loci and copy number
variations causing ASD, which is still growing [18-21].
Environmental causes, such as prenatal exposure to valproate[22-24] and inflammatory insults [25-27], act during theprenatal period in most cases and are thought to affect brain

2. MITOCHONDRIAL FUNCTION-RELATED MTOR
SIGNALING IN AUTISM SPECTRUM DISORDERS

Fig. (1) Association of mTORC1 and mTORC2 in autism spectrum disorders. The genes colored in orange are discussed in the text for thecauses of syndromic ASD. Hyperactivated mTORC1, caused by mutations in the highlighted genes, phosphorylates and alters the function of
the three molecules. First, S6K is activated and global protein synthesis is elevated. Second, 4EBP is inactivated, resulting in releaseinhibition of eIF4E-mediated cap-dependent gene transcription. ULK1 is also activated and autophagy is stimulated though it is unclear
whether this has influence on the genesis of ASD. Akt, protein kinase B; eIF4E, eukaryotic initiation factor 4E; 4EBP, 4E-binding protein;
ERK, extracellular signal-regulated kinase; FMRP, fragile X mental retardation protein; GSK3b, glycogen synthase kinase 3b; IR, insulin
receptor; IRS, insulin receptor substrate; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin; mTORC,
mTOR complex; NF1, neurofibromin; PDK, phosphoinositide dependent kinase; PI3K, phosphatidylinositol 3-kinase; phosphatase andtensin homolog deleted on chromosome 10; RAS, rat sarcoma; Rheb, Ras homolog enriched in brain; S6 ribosomal protein S6; S6K, S6
kinase; TSC, tuberous sclerosis complex; ULK1, unc51-like kinase 1.

Mitochondrial Dysfunction and Its Relationshipdevelopment of brains. Interestingly, the genetic defects
found in individuals with ASD converge on several common
molecular alterations.
One representative alteration is the constitutive activationof mTOR-mediated signaling [14, 28, 29] (Fig. 1). mTOR
plays a central role in cell growth and differentiation. In
neurons, mTOR critically controls synaptic function, and its
alteration is therefore thought to disturb synaptic signaltransmission and result in ASD.
2.1. mTOR Activation and ASD in Monogenic Disorders
2.1.1. mTOR Complexes
Mammalian target of rapamycin (mTOR) interacts withseveral proteins to form two distinct complexes: mTOR
complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
The most distinctive difference between these complexes isthat mTORC1 contains raptor, whereas mTORC2 contains
rictor instead (Fig. 1). mTOR inhibitors such as rapamycin
block mTOR-raptor coupling and inhibit mTORC1 [30, 31]
but not mTORC2, which does not contain raptor. Monogenic
disorders associated with deregulated mTOR-mediatedsignaling have been investigated to reveal the pathogenicrole of mTORC1 in ASD. In this context, tuberous sclerosis
complex (TSC) and PTEN hamartoma tumor syndrome havebeen particularly intensively studied. Activated mTORC1
may participate in ASD in fragile X syndrome (FXS) andneurofibromatosis type 1 (NF1) [14, 28, 29].
2.1.2. The Role of TSC
Tuberous sclerosis complex (TSC) is caused byheterozygous mutations in the TSC1 [32] and TSC2 [33]genes. A hallmark of TSC is the presence of dysplastic andhamartomatous lesions in multiple organs, such as the brain,skin and kidneys [34]. Less specific symptoms frequently
found among TSC individuals include neuropsychiatricproblems such as agitation, hyperactivity and anxiety, which
are collectively known as TSC-associated neuropsychiatricdisorders (TAND) [35]. ASD is one of the most prominentconditions in TAND and makes TSC patients’ daily life
more challenging compared with patients without ASD, bothin school and at home. Approximately half of TSC
individuals have accompanying ASD [14, 36], whereas TSCrelated ASD is found in up to 4% of general ASD cases [20].
TSC is therefore one of the most prevalent genetic causes of
ASD along with FXS (see below). Risk factors for ASD
include low intelligent quality scores, TSC2 mutations,earlier age at seizure onset and infantile spasms (an epileptic
encephalopathy characterized by spasms, hypsarrhythmia in
EEG and developmental arrest or deterioration), whereas theinfluence of the number and location of cortical tubers
remains controversial [14, 36, 38].
Analysis of a rodent model of TSC has contributed to ourunderstanding of how hyperactivated mTOR signaling andthe molecular pathomechanism of TSC participate in thegenesis of ASD. Homozygous mutations in Tsc1 and Tsc2
are embryonically lethal [39, 40]. Haploinsufficient animals
are viable and exhibit no signs of epilepsy, and obvious
lesions are rarely observed in the brains of these mice [39,Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

340] and rats [41, 42]. These rodents show a reduced interest
in social novelty when direct interaction is allowed [43-45],
and an autism-like deficit in social learning is less prominent[21, 46]. They also exhibit signs of cognitive dysfunction
during different behavioral tasks [43, 46, 47]. Treatment
with rapamycin for just a few days completely reverses these
autistic and cognitive deficits in adult mice, demonstrating
the critical role of overactivated mTORC1 [45, 46]. The
selective deletion of TSC genes results in different
phenotypes depending on the targeted cells. Deletion of Tsc1
in Purkinje cells aggravates the approach to a social stimulus[48]. Mice show far more severer phenotypes, such as
epilepsy, brain enlargement and early mortality, when Tsc1
or Tsc2 is eliminated in astrocytes [49] and in neurons of theforebrain [46]. These features are also alleviated by the early
implementation of life-long rapamycin treatment. In a recent
clinical trial of the mTOR inhibitor everolimus, TSC patientswith refractory epilepsy showed a reduction of seizure
frequency as well as improvement of behavioral problems,
including those related to ASD [50]. The above bench andbedside findings suggest that similar to the results in mice,
ASD may be reversible with medication in humans.
2.1.3. Molecular Mechanisms of mTOR
The PTEN (phosphatase and tensin homolog) genenegatively regulates the phosphatidylinositol-4,5-bisphosphate
3-kinase (PI3K) signaling pathway. Deletion of PTEN
releases its inhibition of mTORC1 by activating Akt andinactivating TSC2. Heterozygous mutations in the PTEN
gene can cause several syndromes, whose nomenclaturedepends on the phenotype. Collectively known as PTEN
hamartoma tumor syndrome (PHTS), this group of
syndromes includes Bannayan- Riley-Ruvalcaba syndrome,
Lhermitte-Duclos syndrome and Cowden syndrome [51, 52].
Notably, a subset of ASD individuals with marked
macrocephaly carry Phosphatase and tension homolog
deleted on chromosome ten (PTEN) mutations, irrespectiveof the presence of hamartomas and tumors [53-55],
implicating a direct link between PTEN mutations andmacrocephaly-associated ASD. Similar to TSC, homozygous
deletion of Pten results in embryonic lethality [56]. Pten
heterozygosity in mice reproduces brain enlargement and
ASD in certain settings [13, 57], though these conditions are
subtler than expected compared with the human phenotype.
Deletion of Pten in differentiated neurons of the cerebral
cortex and hippocampus results in overt ASD-like behavioral
deficits as well as epilepsy and early mortality, which areabrogated by chronic treatment with rapamycin beginning in
the early postnatal period [58, 59] Considering the above
evidence in relation to TSC and PTEN, mTOR activation is
likely to be a common molecular event leading to ASD andrepresents a promising therapeutic target.
Several other monogenic disorders, such as FXS and
NF1, are also often associated with ASD. The molecularbasis of neurocognitive deficits in these diseases was initiallyattributed to synaptic transmission via glutamate for FXS
and to the RAS signaling pathway for NF1. ActivatedmTORC1 was subsequently observed in these two disorders,
and research is currently under way to examine its influence.

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FXS is an X-linked disorder caused by the unstable
expansion of a trinucleotide repea in the fragile X mental
retardation 1 (CGG repeat in the FMR1) gene, resulting in
reduced production of the FMRP protein [60]. ASD is foundin approximately half of all male FXS patients and up to 5%
of ASDs derive from FXS; thus, FXS is considered to be themost common monogenic cause of ASD [20, 61].
Investigations on the molecular pathophysiology of FXS
have mainly focused on metabotropic glutamate receptors,
particularly concerning the activation of mGluR5 [62, 63],
and altered mTORC1-mediated signaling has been proposed[14] (Fig. 1). In fragile X mental retardation 1 (Fmr1)
knockout mice, which is a mouse model of FXS, mTORC1
is hyperactivated in the hippocampus [64]. Inhibition ofincreased mTORC1 activity through the genetic removal of
S6K1, a major effector of mTORC1, improves autistic
behavior in these mice [65] (Fig. 1), suggesting a causal roleof the FMRP-mTORC1 interaction in FXS-related ASD.
NF1, an autosomal dominant disorder caused by mutationsin the NF1 gene [66-68], is the most common
neurocutaneous disorder worldwide. Individuals with NF1
often show signs of cognitive deficits in perceptual skills,
executive functions, and attention [69]. Behavioral
alterations relevant to learning deficits in Nf1+/- mice areassociated with increased gamma-amino butyric acid
(GABA)-mediated inhibition and specific deficits in longterm potentiation and can be reversed by decreasing Ras
function [70]. NF1 constitutively activates Extracellular
Signal-regulated Kinase (ERK) [71], and the downstream
signaling pathway in turn suppresses the function of
TSC1/TSC2, leading to mTORC1 activation [72].
Pharmacological inhibition of ERK using statins is effectivein improving cognitive function in mice [73], but its efficacy
is limited in humans [74]. Unlike other disorders mentioned
above, NF1 in relation to ASD has rarely been investigated,partly because the relationship between NF1 and ASD is stillinsufficiently understood. NF1 has long been considered arisk factor for ASD [75]. It was recently revealed that
15-30% of NF1 patients meet the criteria for ASD [76, 77].
Very recently, it was demonstrated that Nf1 haploinsufficiency
causes ASD-like deficits in social learning and aberrant
glutamate and GABA neurotransmission in the amygdala,which can be reversed by pharmacological inhibition as wellas the additional genetic deletion of p21-activated kinase 1(Pak1) [78]. Further research on whether mTORC1
activation is involved in the social deficits observed in NF1
is necessary.
2.2. How does mTORC1 Activation Result in ASD?
2.2.1. mTORC1 Overactivation
Despite the consensus opinion that mTORC1 activation
results in ASD, the immediate molecular events causing
ASD when mTORC1 is constitutively activated in the brain
remain to be elucidated. Analysis of conditional knockout
mouse models of TSC and PHTS revealed that significant
morphological changes are followed by mTORC1
overactivation. Pten deletion in differentiated neurons resultsin neuronal and dendritic hypertrophy, a thickened cerebral
cortex and brain enlargement, followed by profoundphenotypic changes including a reduced survival rate [58,Yui et al.

59]. Inactivation of TSC genes in astrocytes increases
astrocyte proliferation, neuronal disorganization andprogressive macrocephaly [49]. Purkinje cell-specific Tsc1
deletion causes earlier loss of Purkinje cells, an increased
spine density and reduced excitability in Purkinje cells [48].
These genetic manipulations lead to autistic behavior thatcan be rescued by the continuous inhibition of mTORC1
using rapamycin [48, 52]. However, even mice without overt
brain pathologies express social deficits that respond to
rapamycin [39, 40, 45], demonstrating that morphologicalchanges may not be essential for disrupting social behavior.
Another question in this context is what follows mTORC1
activation? mTORC1 regulates many downstream proteins,
including ribosomal p70S6 kinase (S6K1), and eukaryotic
translation initiation factor-4E (4EBP), wchich binds the 5′
cap as a subunit of the eIF4E (Fig. 1). Ribosomal p6 kinase 1(S6K1), when activated by mTORC1, increases protein
synthesis by phosphorylating ribosomal protein S6 [14].
Abnormally enhanced phosphorylation of S6K1 andRibosomal protein S6 (rpS6) may disturb neuronal functions
relevant to ASD via excessive protein production. Anotherpossibility is altered long-term potentiation (LTP).
Hippocampal slices obtained from Tsc2+/- mice show a
reduced threshold of late-phase LTP [28]. Unexpectedly,
S6K1 knockout mice, in which the mTORC1-S6K pathway
is constitutively suppressed, also exhibit deficient social
learning [65] as well as impaired early-phase LTP, without
protein synthesis-dependent late-phase LTP [79]. It has beensuggested that mTORC1-regulated LTP must be carefullybalanced to avoid extremes to support normal social
behavior.
2.2.2. Roles of 4EBPs and eIF4E
Cap-dependent mRNA translation is controlled byeukaryotic translation initiation factor-4E-binding protein(4EBPs) and their target eIF4E. eIF4E interacts with eIF4G
and promotes cap-dependent translation. The 4EBPs bind to
eukaryotic translation initiation factor 4G (eIF4E) andinterrupt the eIF4E-eIF4G interaction, thus resulting indecreased translation. Here, mTORC1 phosphorylates andinhibits the binding of 4EBPs to eIF4E, releases theinhibition of eIF4E, and stimulates cap-dependent mRNAtranslation and protein synthesis [80-82]. An autism-likebehavioral deficit is observed in mice with both 4EBP2
deletion [83] and eIF4E overexpression [84]. This genetic
manipulation enhances the eIF4E-dependent translation of asubset of genes, including neuroligins, and increases spine
density and synaptic activity, resulting in an alteredexcitatory/inhibitory (E/I) ratio. Pharmacological inhibitionof eIF4E normalizes behavioral and neuronal abnormalities[83, 84]. Interestingly, knockdown of neuroligin 1 reverses
neuronal changes and partially rescues social behavior [83].
Upon mTORC1 dysregulation, it has been suggested that
increased synthesis of synaptic proteins, including
neuroligins, disrupts the E/I balance and leads to thedevelopment of an ASD-like phenotype
2.2.3. The Relationship between mTORC1 and mGluR5
Understanding the molecular pathophysiology of FXS
and TSC provides evidence of crosstalk between mTORC1

Mitochondrial Dysfunction and Its Relationshipand metabotropic glutamate receptor 5 (mGluR5) in thebrain. Deletion of the glutamine receptor metabotropic5(Grm5) gene, encoding mGluR5, rescues abnormalities insynaptic density, hippocampal protein synthesis and learningin Fmr1 knockout mice [63]. FXS brains show increased
mTORC1 activity that may be region and age specific [64].
Genetic removal of S6K1 ‒ to cancel out the effect ofmTORC1 activation ‒ reverses the ASD-like phenotype andenhances mGluR5-mediated long-term depression (LTD)[65]. In contrast, mGluR5-mediated LTD is rather attenuatedin Tsc2+/- mice [47, 85]. However, the results have been
inconsistent regarding whether mGluR5 activity is decreased[85] or increased [47] when mTORC1 is activated. The
importance of the mTORC1 – mGluR5 relationship in ASD
may hold true for general ASD. The BTBR mouse strainshows all of the symptoms of ASD [86], which are rescued
by mGluR5 negative allosteric modulation [87].
Furthermore, rapamycin normalizes the associated social
deficit [88]. It should be clarified in more detail how the
ASD-like phenotype can be rescued by mGluR5 modulation(i.e., activated or inactivated, or kept within a certain range).
2.3. Mitochondria, Oxidative Stress and mTOR
2.3.1. mTOR in ASD
An accumulating body of evidence suggests anassociation between ASD and MD. ASD associated withmitochondrial disease is characterized by developmental
regression, elevated plasma lactate and a lack of association
with genetic abnormalities [8]. Elevated plasma lactate isalso observed in general ASD [89, 90]. Analysis of brain
tissue samples revealed that mitochondrial electron transport
chain complexes are reduced in the frontal and temporal
cortices of children with ASD [91]. Impairment of
mitochondrial energy metabolism may underlie general
ASD.
Recently, aberrant macroautophagy was reported in
mTOR-mediated ASD [92]. The authors observed deficient
dendritic pruning and mTOR-dependent macroautophagy inthe post-mortem brains of ASD individuals. Analysis ofmouse models of TSC revealed that mTOR-mediatedmacroautophagy regulates dendritic pruning. Moreover,deletion of Atg7, the gene required for autophagosome
formation, results in deficient social learning andrecapitulates the morphological changes observed in TSC.
However, rapamycin fails to reverse these abnormalities inAtg7-deleted mice. The role of mTORC1-mediatedmacroautophagy in the development of ASD should befurther investigated.
mTORC1 controls mitochondrial functions such as
oxygen consumption, ATP production, fatty acid oxidationand gene transcription [11, 93]. Oxygen consumption and theoxygenation capacity are correlated with mTORC1 activity
and are stimulated by knockdown of Tsc2, but attenuated byknockdown of raptor and S6K1. This is associated with
reduced phosphorylation of enzymes involved in energy
metabolism [93]. Pten deficiency exaggerates mTORC1mediated cap-dependent gene transcription and protein
synthesis, resulting in higher levels of ATP synthesis,
coupled with elevated oxygen consumption [94]. In mice

Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

5lacking Pten in the cerebellum and hippocampus, elevatedrespiratory complex activity is noted from early postnatal
periods. These mice also exhibit autistic behavior at an older
age. This is accompanied by a significant reduction of
mitochondrial DNA levels in the cerebellum andhippocampus, but not in the cortex, where Pten is expressed
normally [13]. It has been suggested that mitochondrial overactivity induced by activated mTORC1 leads tomitochondrial loss and ASD.
2.3.2. mTORC1 Activation
The relationship is also implicated in oxidative stress,
mTORC1 activation and ASD. Neurons lacking the TSC1
and TSC2 genes exhibit higher levels of ROS and expressionof the antioxidant enzyme hemeoxygenase I (HO-1),
indicating increased oxidative stress in the setting of TSC
deficiency [95]. Analysis of lymphoblastoid cell lines(LCLs) revealed an association between an altered redox
status and ASD. LCLs derived from children with ASD
show decreased glutathione concentrations relative tooxidized disulfide glutathione as well as a decreased ratio of
reduced nicotinamide adenine dinucleotide (NADH) to
oxidized NAD+ and higher levels of 3-nitrotyrosine, amarker of protein oxidation that is indicative of chronic
oxidative stress [6, 9, 96]. Compared with control LCLs,
exposure of ASD-derived LCLs to ROS markedly increases
proton leak respiration and markedly depletes the reserve
capacity of mitochondrial respiration. Furthermore, anincrease in baseline ROS production is observed in a
subgroup of ASD-derived LCLs [6]. Therefore, vulnerability
to intrinsic and extrinsic ROS may play a role in theoccurrence of ASD. mTORC1 activation can cause
endoplasmic reticulum (ER) stress. Briefly, excessive protein
synthesis, perturbations in calcium homeostasis, and nutrient
deprivation are some causes of ER stress. Excessive ER
stress activates the unfolded protein response (URP), whichthen stimulates signaling cascades to remove the ER
overload. A failure to eliminate the ER overload results in
ER stress-induced cell death via caspases and theproapoptotic transcription factor CHOP (C/EBP homologous
protein) [95, 97]. Loss of the TSC1 and TSC2 genes coupledwith mTORC1 activation causes ER stress and activates theunfolded protein response (URP) in fibroblasts [97] and in
neurons [95]. Oxidative and ER stress renders neurons
vulnerable to cell death in a CHOP-dependent manner. Cell
death can be rescued by a CHOP inhibitor, but not by
rapamycin [95]. Excessive exposure to oxidative and ER
stress may underlie the genesis of ASD associated with
mTORC1 activation, such as TSC. In these ASD patients,
therapeutic approaches aimed at reducing cellular stressusing antioxidant agents may be beneficial.
In the above sections, we reviewed the complex
associations among ASD, mTORC1 hyperactivation andMD, particularly with regard to the link between ASD andmTORC1. Constitutive activation of mTORC1 may result inoxidative and ER stress as well as ASD associated withmonogenic disorders such as TSC and FXS. In the following
sections, the relationship between ASD and MD is discussed
in more detail.

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3. THE RELATIONSHIP BETWEEN MITOCHONDRIAL DYSFUNCTION AND ANTIOXIDANT ACTIVITY IN AUTISM SPECTRUM DISORDERS
MD includes various pathological features such as
mitochondrial DNA mutations and mitochondrialrespiratory-chain disease. Clinical manifestations related to
the nervous system in primary MD include developmental
regression or delay, seizures, ataxia, movement disorders,
myoclonus and basal ganglia diseases [98]. The prevalenceof MD in the general ASD population has been reported as
5.0% [8], 13.0% [99] or 44% [100]. This indicates thepossibility that a subgroup of children with ASD may have a
new type of MD that is more prevalent and is distinct fromclassic MD [6, 101]. Another study proposed that aneurobiological subtype of ASD should undergo evaluation
for MD [99].
Reports on ASD have generally indicated that oxidative
stress induces ASD due to changes in the antioxidant status[102-104] and heightened vulnerability to oxidative stress[105, 106]. To prevent or reduce reactive oxygen species(ROS) - or MD-induced oxidative stress damage, the humanbody has developed an antioxidant defense system [107].
GSH plays a key role in the cellular defense against oxidant
damage [16]. The oxidative stress-related pathophysiology
of ASD includes MD and impairment of the GSH synthesis
pathway. As mitochondrial oxygen consumption is coupledwith ATP production [108], this review first suggests that theratio of ATP production/oxygen consumption may play a
crucial role in MD.
This chapter discusses four aspects of the relationshipamong MD, impaired GSH biosynthesis and a low
detoxifying capacity against oxidative stress: (1) whether
children with ASD and a concomitant MD might have asubset type of ASD and whether they have a new type ofMD; (2) potential processes that may diverge from theproduction of ROS in the two metabolic pathways, such as
MD and impaired GSH biosynthesis; (3) the relationshipamong the three types of oxidative stress-related
pathophysiologies (MD, impaired GSH synthesis and a low
detoxifying capacity) in ASD; and (4) a summary of theclinical manifestations of ASD with MD and recent data on
the regulation and role and biomarkers of a low detoxifying
capacity, glutathione deletion and MD?.
3.1. Relationship Among Mitochondrial Dysfunction,
Impaired Glutathione Synthesis and A low Detoxifying
Capacity
When antioxidant defenses are weakened, cells andtissues in the body become more prone to dysfunction and/or
disease development [109]. Oxidative modification of
biologically essential molecules by reactive oxygen species(ROS) has been implicated in the pathogenesis of various
diseases [110]. ROS can be neutralized by antioxidant
systems, resulting in a delicate balance that determines thefate and impact of ROS [111]. Oxidative stress-induced cell
death or apoptosis may depend on the cell’s ability to copewith oxidative stress, including its ROS-detoxifying capacity[112], GSH synthesis [113] and mitochondrial function[114].

Yui et al.

3.2. Mitochondrial Dysfunction
Mitochondria are extraordinary organelles that play key
roles in a number of fundamental cellular processes,
including ATP synthesis, ion homeostasis, oxygen sensing[115], and redox homeostasis [116]. Mitochondria areimportant in apoptosis [115, 117], thus participating inneurodegenerative processes [117]. All of these pathways
include redox-reactions as central elements [115].
Mitochondria play an important role in cellular energy bymeans of oxidative phosphorylation, which provides anefficient mechanism coupling electron transport to thesynthesis of ATP [111]. Furthermore, the mitochondrial
electron transport chain plays an important role in thegeneration and management of ROS and the production of
ATP [118]. Thus, synthesis of ATP may be critical in
mitochondrial function [119].
MD occurs as a result of the following changes: (1) lossof maintenance of the electrical and chemical transmembranepotential of the inner mitochondrial membrane, (2)alterations in the function of the electron transport chain, or(3) a reduction of the transport of critical metabolites into
mitochondria [120].
3.2.1. Clinical Manifestations of MD in Individuals with
ASD
Table 1 showed main clinical manifestations of MD. In
Table 2 non-specific clinical signs of MD were presented.
Table 3 showed clinical signs of ASD with a concomitantdiagnosis of MD. MD may present with any symptoms inany organ at any age, but some symptoms and signs are moresuggestive of MD than others. These core features warrant
the initiation of a baseline diagnostic evaluation for
mitochondrial disease (Table 1). In contrast, there are a
multitude of nonspecific symptoms that frequently occur ininfants and children with mitochondrial disease but areassociated with a broad differential diagnoses [98].
Nonspecific findings in MD include neurodegeneration [98],encephalopathy [98], epilepsy [98], ataxia [98], movement
disorders [98], myoclonus, basal ganglia diseases [98],hypotrophic
cardiomyopathy[98],
metaboliccardiomyopathy [121], chronic or cyclic diarrhea andvomiting [121], pseudo-obstruction [121] and diabetes
mellitus [121].
There have been a few prior cohort analyses of MD in
ASD. One previous cohort study involving a review of the
medical records of twenty-five ASD children according to
the DSM-IV-TR identified core clinical manifestations of
MD in individuals with ASD to provide information on theclinical spectrum of individuals with ASD and a concomitantdiagnosis of MD (Table 3) [100]. This cohort study indicatedthat among the twenty-five ASD children aged 2-20 years,
twenty-one had histories of major non-neurological medical
problems. Additionally, twenty-one (84%) exhibited themost common gastrointestinal symptom of constipation;
seventeen (68%) presented excessive fatigability andexercise intolerance; seven (28%) displayed functional
cardiovascular abnormalities (28%); and several exhibitedabnormal findings in physical examinations, including
microcephaly (n=4, 16%), macrocephaly (n=4, 16%) andMitochondrial Dysfunction and Its RelationshipMini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

Table 1.

Main clinical characteristics of mitochondrial dysfunction.

OrgansManifestations

References

Neuromuscular symptoms

Encephaloathy

Hass et al., 2007

7

Basal ganglia disease
Epilepsia partialis continua
AtaxiaNeurodegeneration
Myoclonus
PtosisOphthalmologic abnormalities
Retinal degeneration
Ophthalmoplegia/paresis
Sensorineural deafness

Mattman et al., 2011

Exercise intolerance or myalgia
Developmental delay

Fry and Rossignol, 2011

Loss of skill
SeizureRecurrent or familial neuropathy
Muscle weakness
Gastrointestinal symptoms

Severe dysmotility

Hass et al., 2007

Pseudo-obstructive episode
Constipation

Matman et al., 2012

Diarrhea
Delayed gastric emptying with nausea and vomiting
Cardiovascular

Hypertrophic cardiomyopathy

Hass et al., 2007

Unexplained heart block

Mattman et al., 2011

Metabolic cardiomyopathy
Endocrine

Diabetes mellitus

Mattman et al., 2011

Table 2. Non-specific clinical signs of mitochondrial dysfunction a).
OrgansManifestations

References

Neurologic symptoms

Axonal neuropathyIntractable epilepsy

Hass et al., 2007

Hypotonia
Infantile spasms
Coma
Hearing loss
Gastrointestinal

Chronic or cyclic vomiting

Hass et al., 2007

Cardiovascular

Tachycardia

Hass et al., 2007

Endocrine

Hypothyroidism

Hass et al., 2007

Hypoparathyroidism
Idiopathic growth hormone deficiency
Renal

Renal tubular dysfunction

Hass et al., 2007

Nephrotic syndromea) Non-specific clinical sighs indicate other clinical characteristics that frequently occur in children with mitochondrial dysfunction but have a broad different diagnosis, and more
often lead to other clear diagnosis (Haas et al., 2007).

8

Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

Table 3.

Yui et al.

Clinical signs of autism spectrum disorders accompanied by mitochondrial dysfunction.
Weissman et al., 2008
(N = 25)

Rossignol and Frye, 2012
(N = 68)

Palieri and Persico, 2010
(N = 25)

Shoffner et al., 2010
(N = 28)

At least 1 non-CNS organ system

84

-

-

-

Fatigability or exercise intolerance

68

54

76

42.9

Gastrointestinal dysfunction

64

74

64

-

Constipation

20

-

-

-

At least 1 neurological finding of
uncommon ASD

60

58a)

-

-

Multiple regression

38

-

-

-

Gross developmental motor delay

32

51

32

46.4

Regression

24

52

-

-

Seizure

20

41

39.3

-

Growth retardation

20

21

20

10.7

Oculomotor abnormality

16

-

-

-

Macrocephaly

16

16

-

-

Microcephaly

16

16

-

-

Sensorineural hearing deficit

12

-

-

-

Dysarthria

12

-

-

-

Movement disorders

8

-

-

-

Hypotonia

62

-

-

-

Ataxia

58

-

-

-

Cardiomyopathy

24

-

-

-

Endocrine dysfunction

8

-

-

-

Renal dysfunction

8

-

-

-

Hematologic abnormality

8

-

-

-

Ptosis

8?

-

-

-

Values are expressed as percent of patients. a) ataxia.

growth retardation (n=5, 20%). In this study, twelve patients
presented neurological findings that are uncommon in ASD(n=12, 48%), including oculomotor abnormalities (n = 4,16%), sensorineural hearing deficits (n = 3, 12%), dysarthria(n = 3, 12%), ptosis (n = 2, 8%), and movement disorders(n = 2), and five patients (20%) had seizures, one of whom
had medically refractory epilepsy. Eight patients exhibited
markedly delayed early motor milestones (32%). Fourteen
patients showed regression of previously acquired skills(56%), with nine presenting multiple regressions (36%), six
presenting regression at ages older than three years (24%),and seven presenting regressions occurring with infections orother metabolic stresses (28%). In six patients, gross motor
skills were lost in addition to language skills (24%). In one
case, the timing of regression coincided with a recent
vaccination (4%) [100] (Table 3). Overall, the main clinicalmanifestations in individuals with ASD/MD were found tobe the gastrointestinal symptom of constipation, regressionof previously acquired skills, neurological abnormalities,
delayed motor milestones, excessive fatigability, exercise
intolerance, functional cardiovascular abnormalities,
dysmorphisms such as macrocephaly and microcephaly, andmedically refractory epilepsy.
These features are similar to the features of MD, as
shown in Tables 2 and 3. In previous studies, MD features
have been diagnosed in ASD patients with a range ofincidences: 5.0% of 68 ASD children and adolescents, withthe oldest being 20 years of age [8]; 13.0% of individuals
with ASD aged 5 to 60 years of age [99]; 19% of 210 ASD
patients [122]; and 45% of ASD children aged 11 to 14 yearsof age [123] were diagnosed as having MD features. The
above findings, together with a previous report indicatingthat that MD presents clinically in at least one in 10,000
adults [124], suggest that individuals with ASD and aMitochondrial Dysfunction and Its RelationshipMini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

9

Fig. (2). Oxidative stress in autism spectrum disorder. The arrows in the figure represent the advanced oxidation processes. The ratio of ATP
production/oxygen consumption may be a potential candidate target for preventing MD due to oxidative stress. On the other hand, disruptionof ATP synthesis alone may be related to impaired GSH synthesis. In this regard, oxygen consumption may be important in preventing MD.
ROS, reactive oxygen species; ATP, adenosine triphosphate; SOD, superoxide dismutase; ASD, autism spectrum disorders.

concomitant diagnosis of MD are more prevalent thanpatients with typical MD. Collectively, a significant
subgroup of ASD children may have a new type of MD thatis more prevalent and is distinct from classic MD [7, 9].
Meanwhile, another study suggested that children with ASD
and a concomitant diagnosis of MD may constitute a subsetof the ASD population who have distinct abnormalities inredox metabolism such as MD [101]. In this regard, aprevious study reported the interesting finding that seventyfive individuals with ASD (simplex type) aged 5-60 years
exhibited lactate-positive voxels in the cingulate gyrus more
frequently, indicating that these autistic individuals with aconcomitant diagnosis of MD may be a neurobiologicalsubtype of ASD [99]. However, only 60% of autistic
individuals ASD with a concomitant diagnosis of MD show
developmental regression including impaired social
communication, but not stereotyped or repetitive behaviors[100]. Moreover, autistic individuals with a concomitantdiagnosis of MD display clinical manifestations including
prevalent seizures [98] and exhibit abnormal biochemicalmarkers of MD [8, 98]. The DSM-IV criteria do not include
major neurological and non-neurological medical problems(e.g., constipation in the gastrointestinal system, excessive

fatigability, exercise intolerance, and cardiovascular functional
abnormalities). It would therefore be logical to propose that
autistic individuals with MD may have a subtype of MD thatis more prevalent and is distinct from classic MD.
Considering that tuberous sclerosis and the Landau-Kleffner
syndrome manifest with similar symptoms to ASD,
individuals with ASD/MD are more likely to represent a new
type of MD. This review proposes that individuals with ASD
and a concomitant diagnosis of MD may exhibit a subtype of
MD rather than a subtype of ASD.
3.2.2. Biomarkers of ASD with a Concomitant Diagnosis of
MD
Table 4 shows the number of subjects exhibiting
abnormal results for biochemical markers of ASD with aconcomitant diagnosis of MD, along with the mainreferences published during 2008-2012 [8, 100, 125-127].
The abnormal biochemical parameters that are frequently
detected in ASD with MD include elevated blood or plasma
levels of lactate and an increased lactate/pyruvate ratio [8,100, 126]. Lactate has long been regarded as an end productof anaerobic energy production and appears to play an10 Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

Table 4.

Yui et al.

Biochemical data from individuals with ASD accompanied by MD.

Biochemical markers

Number of abnormal

Weissman et al., 2008

Number abnormal/number tested

Increased blood lactate

19/25 (76%)

Increased serum aspartate transaminase or alanine transaminase

13/25 (53%)

Increased plasma pyruvate acid

9/17 (53%)

Abnormal urinary organic acid analysis

10/24 (42%)

Increased plasma alanine

9/25 (36%)

Increased serum creatine kinase

8/25 (32%)

Increased fibroblast lactate/pyruvate ratio

3/15 (20%)

Increased lactate on cranial MRS

10/21 (40%)

Shoffner et al., 2010
Increased blood lactate, pyruvate and alanine

13/28 (46.4)

Palmieri et al., 2010‡
Increased plasma lactate

15/15 (100.0%)

Decreased plasma GSH

148/233 (63.5%)

Increased plasma GSSG

118/203 (58.4%)

Increased MDA

67/67 (100.0%)

Essa et al., 201219 ASD children vs 19 normal controls
Plasma levels of PCO, LPO, and lactate/pyruvate ratio significant decreases in ASD children
Rossignol and Frye, 2012†
Elevated lactate

31.1%

Elevated pyruvate

13.6%

Elevated lactate/pyruvate ratio

27.6%

Elevated creatine kinase

46.8%

Elevated ammonia

35.0%

Elevated AST

45.6%

Elevated ALT

7.0%

Low total carnitine

90.0%†, The total number of subjects was not described (Weissman et al., 2012); ‡, total number who exhibited abnormal values (Palmieri et al., 2010).
PCO, protein carbonyls; LPO, lipid peroxidation; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

important role in the antioxidant defense [129]. The plasma
lactate concentration is a marker of the severity of the tissue
oxygen supply-to-demand imbalance [130]. Pyruvate is theend product of cytosolic glycolysis and has a variety ofpossible fates, with the major one being mitochondrial
oxidation [131] (Table 4). Thus, a high blood lactate/pyruvate ratio is a potential biomarker of MD [132].
Additionally, aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) are biochemical markers of organ
dysfunction, including MD [133].

mitochondrial electron transport chain and DHA, has beensuggested to be a potential therapeutic agent for Alzheimer's
disease, as it may restore the decreased oxygen consumption
rate and ATP turnover [134]. Quercetin potentially prevents
Huntington’s disease and other neurodegenerative disordersin which mitochondrial function is perturbed [135].
Resveratrol treatment functionally impacts oxygen
consumption and mitochondrial ATP production while
decreasing lactate contents, thus showing potential clinicalapplications in selected Parkinson’s disease patients [136].

3.2.3. Medical Treatment of MD

3.3. Impairment of Glutathione Biosynthesis

Accumulating evidence indicates that essential cofactors
in mitochondria and certain types of flavone and plantcompounds are effective for treating MD. Beta-amyloid (Aβ)
protein is a key factor in the pathogenesis of Alzheimer's
disease. Coenzyme Q10, an essential cofactor involved in the

3.3.1. Glutathione Synthesis
GSH in the mitochondria controls compartment-specificneeds and functions [111], representing the main mechanismof antioxidant defense against ROS [111]. Thus, GSH

Mitochondrial Dysfunction and Its RelationshipMini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

11

deficiency can lead to impaired mitochondrial function [111,128]. The synthesis of GSH from glutamate, cysteine, andglycine is catalyzed sequentially by two cytosolic enzymes,
γ-glutamylcysteine synthetase and GSH synthetase [137].

behavioral sequences described in the DSM-5 criteria for
autistic disorders.

Upon reaction with ROS, GSH becomes oxidized to
GSSR by GSSH reductase (GR), a process that decreases
GSH [111, 138]. The ratio of reduced GSH to the oxidized
disulfide form of glutathione (i.e., glutathione disulfide,
GSSH) is considered to be a reproducible indicator of thesystemic redox status that can be used to clinically assess
and treat individuals with ASD, who may be at risk ofoxidative stress-related pathology [139]. Moreover, the
GSH/GSSH ratio reflects the oxidative state and interactions
with ROS to the maintain redox balance in the cell [111]. A
shift in the GSH redox rate towards to the oxidized state maylead to DNA damage and increased apoptosis [138].

Plasma 3CT [142], S- adenosylmethionine (SAM) and Sadenosylhomocysteine (SAH) [144, 147] are usefulbiomarkers of impaired GSH synthesis and treatment status
in ASD.

3.3.2. Clinical Findings
As a decreased GSH redox ratio has been reported inindividuals with ASD, it has been hypothesized that a shift in
the GSH redox ratio may play a role in the etiology of ASD[138, 140]. Some evidence has suggested that glutathione
redox ratios, such as the GSH/GSSH ratio, can be used as
biomarkers of impaired GSH synthesis and treatment status
in ASD [141, 142]. An early study examined 20 children
with ASD with a mean age of 6.4±1.5 years who met theDSM-IV criteria for autistic disorders. Most of thesechildren exhibited symptoms of gastrointestinal distress, inaddition to impaired speech and socialization skills. In thisstudy, plasma levels of GSH and the GSH/GSSH ratio were
found to be reduced [143]. Two other studies examined
glutathione redox status and glutathione metabolism, in 40
children [143] and 48 children [142] who met the DSM-IV
criteria of autistic disorders. In these two studies, Asperger’s
disorder, pervasive developmental disorders (not otherwise
specified), severe gastrointestinal distress, genetic disorders
and chronic seizures (epilepsy) were excluded. In thesestudies, the total GSH/GSSH ratio was shown to besignificantly reduced compared with 42 (James et al., 2009)[144] and 40 age-matched normal controls [142]. The mostrecent of these studies, in which the diagnostic criteria
included the DSM-5 criteria for autistic disorders but
excluded epileptic seizure and any additional psychiatric andneurological disorders, revealed lower plasma levels of
glutathione-transferase compared with 30 age-matchednormal controls [145]. Another earlier study examinedfrozen samples from the cerebella and temporal cortexes offifteen individuals with ASD and twelve unaffected controls[141]. In this study, the diagnosis of ASD was confirmed
based on the Autism Diagnostic Interview-Revised, whichmatches the DSM-5 criteria for ASD symptoms without any
neurological or somatic symptoms [146]. This study reported
that the cerebella of ASD individuals show significantly
decreased GSH levels, GSH/GSSH ratios and mitochondrialsuperoxide production as well as significantly increased
levels of biomarkers of oxidative stress, such as 3nitrotyrosine (3-NT), and inflammation, such as 3chlorotyrosine (3-CT) [141] Considering these findings
together, this review is the first to suggest that impaired GSH
synthesis is evident in relation to the core social and3.3.3. Biomarkers of Impaired GSH Synthesis

3.4. The Role of ATP in MD and Impaired GSH
Synthesis
Mitochondria play an important role in ATP generation[148]. An imbalance between energy intake and expenditureleads to MD, characterized by a reduced ratio of energy
production, such as ATP production [149]. In the cytosol,
GSH synthesis includes two consecutive ATP-dependent
enzymatic reactions. The first step in GSH synthesis
involves the formation of glutamylcysteine from glutamate
and cysteine in an ATP-dependent reaction catalyzed byglutamate-cystein-ligase [138]. In the second step, γglutamylcysteine (GCL) is coupled to glycine to form GSH
via glutathione synthetase [138, 140]. The major
determinants of GSH synthesis are the availability ofcysteine and glutamate cysteine ligase [140, 150]. When
oxidative stress coincides with excess dietary nutrients,
glycolytically synthesized ATP inhibits mitochondrial
oxygen consumption [119]. Importantly, when nutrient
oxidation is insufficient, the ratio of ATP synthesis/oxygen
consumption is low, leading to increased production of ROS,
such as superoxide anions [149]. Mitochondrial oxygen
consumption is uncoupled from ATP production during theformation of reactive oxygen species by components of themitochondrial electron transport chain [108]. It therefore
appears that ATP production/oxygen consumption may beclosely associated with MD. Hence, this review provides apotential framework to explain how the ratio of ATP
production/oxygen consumption may be a potential
candidate target for preventing MD due to oxidative stress.
On the other hand, disruption of ATP synthesis alone may berelated to impaired GSH synthesis. In this regard, oxygen
consumption may be important in preventing MD.
3.5. Impairment of the Antioxidant Capacity
An adequate equilibrium between the production of ROS
and the antioxidant capacity plays an important role in brain
function. In this context, early studies on ASD mostly
reported that changes in the blood levels of SOD, Tf and Cp
indicate alterations of the antioxidant status [102-104],
vulnerability to oxidative stress [105, 106], and copper
dyshomeostasis [151, 152] in children with ASD. Although
ASD consists of a group of developmental disorders withsymptoms that present in a continuum ranging from mild tosevere expression [153], the core symptoms of ASD include
two domains according to the DSM-5 [7]: negative
symptoms of impairment of social and communication
function impairment and positive symptoms of restricted andrepetitive behaviors in the DSM-5. The DSM-5 does notincludes any major neurological and non-neurological
medical problems in the diagnostic criteria for ASD [7].

12 Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

Participants in these earlier studies exhibited the core
symptoms, such as social and communication impairment.
The plasma [106, 152, 154, 155] and urinary [156, 157]
total antioxidant capacity (TAC) are useful biomarkers of
reduced antioxidant capacity. A few studies have examined
plasma or urinary levels of TAC in ASD. A previous study
found that plasma TAC levels were reduced in 35
individuals with Asperger’s disorders compared with 34 agematched normal healthy controls [106]. In addition, urinarylevels of TAC were reported to be elevated in 45 autistic
children aged 4-12 years [156] and 29 children with ASD
aged 6-12 years [157]. Salivary TAC was shown to besignificantly reduced in 101 children aged 2-12 years [158].
The exclusion criteria for these studies included neurologicaldisorders and a history of head trauma [106]. Participants in
the remaining two studies met the DSM-IV-TR criteria for
autism [157] or were scored using the Childhood Autism
Rating Scale [156] and therefore did not exhibit any major
neurological or non-neurological medical problems.
Collectively, these findings appear to indicate that reduced
plasma or urinary TAC levels occur in ASD children without
any neurological or somatic symptoms.

Yui et al.

LIST OF ABBREVUATIONS
ALT= Alanine aminotransferase

ASD= Autism spectrum disorders

AST= Aspartate aminotransferase

ATP= Adenosine triphosphate

CGG repeat in
the FMR1= Trinucleotide repeat in the fragile X
mental retardation
CHOP= C/EBP homologous protein

3-CT= 3-chlorotyrosine

eIF4E= Eukaryotic translation initiation factor 4E

eIF4G= Eukaryotic translation initiation factor 4G

ER= Endoplasmic reticulum

ERK= Extracellular Signal-regulated Kinase

4EBPs= Eukaryotic translation initiation factor 4E(eIF4E)-binding proteins

Fmr1= Fragile X mental retardation 1

4. CONCLUSIONSFMRP= Fragile X Mental Retardation Protein

Mitochondria are organelles that play a central role inprocesses related to cellular viability, such as energy
production, cell growth, cell death via apoptosis, andmetabolism of reactive oxygen species (ROS). Constitutive
activation of mTORC1 may result in oxidative and ER stressas well as ASD associated with monogenic disorders such as
TSC and FXS. We can observe behavioral abnormalities
relevant to autism spectrum disorders (ASDs) and theirrecovery mediated by the mTOR inhibitor rapamycin inmouse models. In Tsc2+/- mice, the transcription of multiple
genes involved in mTOR signaling is enhanced, suggesting a
crucial role of dysregulated mTOR signaling in the ASD
model. Moreover, The mTOR inhibitor such as rapamycin
may be useful target for the pharmacological treatment oftreatment resistant ASD.

FXS

= Fragile X syndrome

GABA= Gamma-aminobutyric acid

GCL

= γ-glutamylcysteine

GMR 5= Glutamine receptor metabotropic 5

GR= GSSH reductase (GR)GSH

= Glutathione

GSSH= Glutathione disulfide

HO-1= Heme oxygenase I

LCLs= Lymphoblastoid cell lines

LTD= Long-term depression

This review offers three insights into the relationshipbetween MD and impaired GSH synthesis. Firstly, children
with ASD and concomitant diagnosis of MD have beenreported to manifest clinical manifestations similar to thoseof MD, and it therefore appears that the clinicalmanifestations of ASD with a concomitant diagnosis of MD
are more likely to be due to MD. Secondly, the ATPproduction/oxygen consumption ratio may be a potential
candidate target for preventing MD due to oxidative stress,
and the disruption of ATP synthesis alone may be related to
impaired GSH synthesis. Third, changes in TAC have beenreported in most ASD children without any neurological andsomatic symptoms. In future studies, these three types ofpathophysiologies should be considered throughout thepathophysiology and medical treatment of ASD. This
information provides insight into the pathophysiology of
ASD and can guide the design of medical treatments forvarious subtypes of ASD.

MD

= Mitochondrial dysfunction

mGluR5= Metabotropic glutamate receptor 5

mTOR= Mammalian target of rapamycin

NAD= Nicotinamide adenine dinucleotide

NADH= Nicotinamide adenine dinucleotide

NF1= Neurofibromatosis type 1

3-NT= 3-nitrotyrosine

PHTS= PTEN hamartoma tumor syndrome

PTEN= Phosphatase and tension homolog deleted
on chromosome ten

ROS= Reactive oxygen species

rpS6= Ribosomal protein S6

S6K1= Ribosomal p6 kinase 1

Mitochondrial Dysfunction and Its RelationshipMini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

SAH= S-adenosylhomocysteine

SAM= S-adenosylmethionine

TAC= Total antioxidant capacity

TSC= Tuberous sclerosis complex

URP= Unfolded protein response

mice with social deficits and repetitive behavior: interplay between
Pten and p53. PLoS One, 2012, 7(8), e42504.
de Vries, P.J.; Howe, C.J. The tuberous sclerosis complex proteins- a GRIPP on cognition and neurodevelopment. Trends Mol. Med.,2007, 13, 319-326.
Tang, B.; Dong, X.; Wei, Z.; Qiao, H.; Jiang, H.; Liu, B.; Sun, X.
Enhanced autophagy by everolimus contributes to the antirestenotic
mechanisms in vascular smooth muscle cells. J. Vasc. Res., 2014,
51(4), 259-68.
Enns, G.M.; Moore, T.; Le, A.; Atkuri, K.; Shah, M.K.; CusmanoOzog, K.; Niemi, A.K.; Cowan, T.M. Degree of glutathione
deficiency and redox imbalance depend on subtype of
mitochondrial disease and clinical status. PLoS One, 2014; 9(6),e100001.
Naviaux, R.K. Oxidative shielding or oxidative stress? J.
Pharmacol. Exp. Ther., 2012, 342(3), 608-618.
Abrahams, B.S.; Geschwind, D.H. Advances in autism genetics: onthe threshold of a new neurobiology. Nat. Rev. Genet., 2008, 9,341-355.
Pinto, D.; Pagnamenta, A.T.; Klei, L.; Anney, R.; Merico, D.;
Regan, R.; Conroy, J.; Magalhaes, T.R.; Correia, C.; Abrahams,
B.S.; Almeida, J.; Bacchelli, E.; Bader, G.D.; Bailey, A.J.; Baird,G.; Battaglia, A.; Berney, T.; Bolshakova, N.; Bölte, S.; Bolton,
P.F.; Bourgeron, T.; Brennan, S.; Brian, J.; Bryson, S.E.; Carson,
A.R.; Casallo, G.; Casey, J.; Chung, B.H.; Cochrane, L.; Corsello,C.; Crawford, E.L.; Crossett, A.; Cytrynbaum, C.; Dawson, G.; deJonge, M.; Delorme, R.; Drmic, I.; Duketis, E.; Duque, F.; Estes,
A.; Farrar, P.; Fernandez, B.A.; Folstein, S.E.; Fombonne, E.;
Freitag, C.M.; Gilbert, J.; Gillberg, C.; Glessner, J.T.; Goldberg, J.;
Green, A.; Green, J.;. Guter, S.J.; Hakonarson, H.; Heron, E.A.;
Hill, M.; Holt R.; Howe, J.L.; Hughes, G.; Hus, V.; Igliozzi, R.;
Kim, C.; Klauck, S.M.; Kolevzon, A.; Korvatska, O.; Kustanovich,
V.; Lajonchere, C.M.; Lamb, J.A.; Laskawiec, M.; Leboyer, M.; Le
Couteur, A.; Leventhal, B.L.; Lionel, A.C.; Liu, X.Q.; Lord, C.;
Lotspeich, L.; Lund, S.C.; Maestrini, E.; Mahoney, W.; Mantoulan,C.; Marshall, C.R.; McConachie, H.; McDougle, C.J.; McGrath, J.;
McMahon, W.M.; Merikangas, A.; Migita, O.; Minshew, N.J.;
Mirza, G.K.; Munson, J.; Nelson, S.F.; Noakes, C.; Noor, A.;
Nygren, G.; Oliveira, G.; Papanikolaou, K.; Parr, J.R.; Parrini, B.;
Paton, T.; Pickles, A.; Pilorge, M.; Piven, J.; Ponting, C.P.; Pose,
D.J.; Poustka, A.; Poustka, F.; Prasad, A.; Ragoussis, J.; Renshaw,
K.; Rickaby, J.; Roberts, W.; Roeder, K.; Roge, B.; Rutter, M.L.;
Bierut, L.J.; Rice, J.P.; Salt, J.; Sansom, K.; Sato, D.; Segurado, R.;
Sequeira, A.F.; Senman, L.; Shah, N.; Sheffield, V.C.; Soorya, L.;
Sousa, I.; Stein, O.; Sykes, N.; Stoppioni, V.; Strawbridge, C.;
Tancredi, R.; Tansey, K.; Thiruvahindrapduram, B.; Thompson,
A.P.; Thomson, S.; Tryfon, A.; Tsiantis, J.; Van Engeland, H.;
Vincent, J.B.; Volkmar, F.; Wallace, S.; Wang, K.; Wang, Z.;
Wassink, T.H.; Webber, C.; Weksberg, R.; Wing, K.; Wittemeyer,
K.; Wood, S.; Wu, J.; Yaspan, B.L.; Zurawieck, D.; Zwaigenbaum,
L.; Buxbaum, J.D.; Cantor, R.M.; Cook, E.H.; Coon, H.; Cuccaro,
M.L.; Devlin, B.; Ennis, S.; Gallagher, L.; Geschwind, D.H.; Gill,M.; Haines, J.L.; Hallmayer, J.; Miller, J.; Monaco, A.P.;
Nurnberger, J.I Jr.; Paterson, A.D.; Pericak-Vance, M.A.;
Schellenberg, G.D.; Szatmari, P.; Vicente, A.M.; Vielan, V.J.;
Wijsman, E.M.; Scherer, S.W.; Sutcliffe, J.S.; Betancur, C.
Functional impact of global rare copy number variation in autism
spectrum disorders. Nature, 2010, 466, 368-372.
Caglayan, A.O. Genetic causes of syndromic and non-syndromic
autism. Dev. Med. Child Neurol., 2010, 52, 130-138.
Misra, V. The social brain network and autism. Ann. Neurosci.,
2014, 21, 69-73.
Wagner, G.C.; Reuhl, K.R.; Cheh, M.; McRae, P.; Halladay, A.K.
A new neurobehavioral model of autism in mice: pre- and postnatal
exposure to sodium valproate. J. Autism Dev. Disord., 2006, 36,
779-93.
Meador, K.J.; Baker, G.A.; Browning, N.; Cohen, M.J.; Bromley,
R.L.; Clayton-Smith, J.; Kalayjian, L.A.; Kanner, A.; Liporace,
J.D.; Pennell, P.B.; Privitera, M.; Loring, D.W.; NEAD Study
Group. Fetal antiepileptic drug exposure and cognitive outcomes atage 6 years (NEAD study): a prospective observational study.
Lancet Neurol., 2013, 12, 244-252.
Christensen, J.; Grønborg, T.K.; Sørensen, M.J.; Schendel, D.;
Parner, E.T.; Pedersen, L.H.; Vestergaard, M. Prenatal valproate

[14]
[15]

[16]

CONFLICT OF INTEREST
The authors confirm that this article content has noconflict of interest.
ACKNOWLEDGEMENTS
Dr. Kunio Yui received a Grant-in-Aid For Scientific
Research on Innovative Areas (Grant No 21200017) from
the Ministry of Education, Culture, Sports, Science andTechnology, Japan (2009-2012), and a Grant-in-Aid For
Scientific Research C (2014-2017)

[17]
[18]
[19]

REFERENCES
[1]

[2]

[3]

[4]

[5]
[6]

[7]
[8]
[9]

[10]

[11]

[12]
[13]

De Felice, F.G.; Ferreira, S.T. Inflammation, defective insulin
signaling, and mitochondrial dysfunction as common moleculardenominators connecting type 2 diabetes to Alzheimer disease.
Diabetes, 2014, 63, 2262-2272.
Stroh, M.; Swerdlow, R.H.; Zhu, H. Common defects ofmitochondria and iron in neurodegeneration and diabetes (MIND):
a paradigm worth exploring. Biochem. Pharmacol., 2014, 88, 573583.
Goto, Y.; Horai, S.; Matsuoka, T.; Koga, Y.; Nihei, K.; Kobayashi,M.; Nonaka, I. Mitochondrial myopathy, encephalopathy, lactic
acidosis, and stroke-like episodes (MELAS): a correlative study ofthe clinical features and mitochondrial DNA mutation. Neurology,
1992, 42, 545-550.
Shoffner, J.M.; Lott, M.T.; Lezza, A.M.; Seibel, P.; Ballinger,
S.W.; Wallace, D.C. Myoclonic epilepsy and ragged-red fiber
disease (MERRF) is associated with a mitochondrial DNAtRNA(Lys) mutation. Cell, 1990, 61, 931-937.
Chaturvedi, R.K.; Flint Beal, M. Mitochondrial diseases of thebrain. Free Radic. Biol. Med., 2013, 63, 1-29.
Rose, S.; Frye, R.E.; Slattery, J.; Wynne, R.; Tippett, M.; Melnyk,
S.; James, S.J. Oxidative stress induces mitochondrial dysfunction
in a subset of autistic lymphoblastoid cell lines. Transl. Psychiatry,
2014a, 4:e377.
American Psychiatric Association. (2013). Diagnostic andstatistical manual of mental disorders, 5th ed.; Arlington, VA:
American Psychiatric Publishing, 2013.
Rossignol, D.A.; Frye, R.E. Mitochondrial dysfunction in autism
spectrum disorders: a systematic review and meta-analysis. Mol.
Psychiatry, 2012, 17(3), 290-314.
Rose, S.; Frye, RE.; Slattery.; Wynne, R.; Tippett, M.; Pavliv, O.;
Melnyk, S.; James, S.J. Oxidative stress induces mitochondrial
dysfunction in a subset of autism lymphoblastoid cell lines in awell-matched case control cohort. PLoS One, 2014b, 9(1), e85436.
Schieke, S.M.; Phillips, D.; McCoy, J.P.; Jr, Aponte, A.M.; Shen,
R.F.; Balaban, R.S.; Finkel, T. The mammalian target of rapamycin(mTOR) pathway regulates mitochondrial oxygen consumption andoxidative capacity. J. Biol. Chem., 2006, 281, 27643-27652.
Cunningham, J.T.; Rodgers, J.T.; Arlow, D.H.; Vazquez, F.;
Mootha, V.K.; Puigserver, P. mTOR controls mitochondrial
oxidative function through a YY1-PGC-1alpha transcriptional
complex. Nature, 2007, 450, 736-740.
Goo, C.K.; Lim, H.Y.; Ho, Q.S.; Too, H.P.; Clement, M.V.; Wong,
K.P. PTEN/Akt signaling controls mitochondrial respiratory
capacity through 4E-BP1. PLoS One, 2012, 7(9), e45806.
Napoli, E.; Ross-Inta, C.; Wong, S.; Hung, C.; Fujisawa, Y.;
Sakaguchi, D.; Angelastro, J.; Omanska-Klusek, A.; Schoenfeld,
R.; Giulivi, C. Mitochondrial dysfunction in Pten haplo-insufficient

[20]
[21]
[22]

[23]

[24]

13

14 Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

[25]
[26]
[27]

[28]
[29]
[30]

[31]

[32]

[33]
[34]

[35]

[36]
[37]
[38]

[39]

[40]

[41]

[42]

exposure and risk of autism spectrum disorders and childhood
autism. J.A.M.A., 2013, 309, 1696-1703.
Shi, L.; Fatemi, S.H.; Sidwell, R.W.; Patterson, P.H. Maternal
influenza infection causes marked behavioral and pharmacologicalchanges in the offspring. J. Neurosci., 2003, 2, 297-302.
Smith, S.E.; Li, J.; Garbett, K.; Mirnics, K.; Patterson, P.H.
Maternal immune activation alters fetal brain development throughinterleukin-6. J. Neurosci., 2007, 27, 10695-10702.
Meldrum, S.J.; Strunk, T.; Currie, A.; Prescott, S.L.; Simmer, K.;
Whitehouse, A.J. Autism spectrum disorder in children born
preterm-role of exposure to perinatal inflammation. Front.
Neurosci., 2013, 7, 123.
Ehninger, D.; Silva, A.J. Rapamycin for treating tuberous sclerosis
complex and autism spectrum disorders. Trends Mol. Med., 2011,
17, 78-87.
Sawicka, K., Zukin, R.S. Dysregulation of mTOR signaling inneuropsychiatricdisorders:therapeutic
implications.
Neuropsychopharmacology, 2012, 37, 305-306.
Kim, D.H.; Sarbassov, D.D.; Ali, S.M.; King, J.E.; Latek, R.R.;
Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. mTOR
interacts with raptor to form a nutrient-sensitive complex thatsignals to the cell growth machinery. Cell, 2002, 110, 163-175.
Hara, K.; Maruki, Y.; Long, X.; Yoshino, K.; Oshiro, N.; Hidayat,
S.; Tokugaga, C.; Avruch, J.; Yonezawa, K. Raptor, a binding
partner of target of rapamycin (TOR), mediates TOR action. Cell,
2002, 110, 177-789.
van Slegtenhorst, M.; de Hoogt, R.; Hermans, C.; Nellist, M.;
Janssen, B.; Verhoef, S.; Lindhout, D.; van den Ouweland, A.;
Halley, D.; Young, J.; Burley, M.; Jeremiah, S.; Woodward, K.;
Nahmias, J.; Fox, M.; Ekong, R.; Osborne, J.; Wolfe, J.; Povey, S.;
Snell, R.G.; Cheadle, J.P.; Jones, A.C.; Tachataki, M.; Ravine, D.;
Sampson, J.R.; Reeve, M.P.; Richardson, P.; Wilmer, F.; Munro,C.; Hawkins, T.L.; Sepp, T.; Ali, J.B.; Ward, S.; Green, A.J.; Yates,
J.R.; Kwiatkowska, J.; Henske, E.P.; Short, M.P.; Haines, J.H.;
Jozwiak, S.; Kwiatkowski, D.J. Identification of the tuberous
sclerosis gene TSC1 on chromosome 9q34. Science, 1997, 277,805-808.
European Chromosome 16 Tuberous Sclerosis Consortium.
Identification and characterization of the tuberous sclerosis gene on
chromosome 16. Cell, 1993, 75, 1305-1315.
Northrup, H.; Krueger, D.A. International Tuberous Sclerosis
Complex Consensus Group. Tuberous sclerosis complex diagnostic
criteria update: recommendations of the 2012 Iinternational
Tuberous Sclerosis Complex Consensus Conference. Pediatr.
Neurol., 2013, 49, 243-254.
Krueger, D.A.; Northrup, H. International Tuberous Sclerosis
Complex Consensus Group. Tuberous sclerosis complex
surveillance and management: recommendations of the 2012
International Tuberous Sclerosis Complex Consensus Conference.
Pediatr. Neurol., 2013, 49, 255-265.
Lewis, J.C.; Thomas, H.V.; Murphy, K.C.; Sampson, J.R.
Genotype and psychological phenotype in tuberous sclerosis. J.
Med. Genet., 2004, 41(3), 203-207.
Caglayan, A.O. Genetic causes of syndromic and non-syndromic
autism. Dev. Med. Child Neurol., 2010, 52(2), 130-138.
Numis A.L.; Major, P.; Montenegro, M.A.; Muzykewicz, D.A.;
Pulsifer, M.B.; Thiele, E.A. Identification of risk factors for autism
spectrum disorders in tuberous sclerosis complex. Neurology, 2011,76, 981-987.
Kobayashi, T.; Minowa, O.; Kuno, J.; Mitani, H.; Hino, O.; Noda,
T. Renal carcinogenesis, hepatic hemangiomatosis, and embryoniclethality caused by a germ-line Tsc2 mutation in mice. Cancer
Res., 1999, 59, 1206-1211.
Kobayashi, T.; Minowa, O.; Sugitani, Y.; Takai, S.; Mitani, H.;
Kobayashi, E.; Noda, T.; Hino, O. A germ-line Tsc1 mutation
causes tumor development and embryonic lethality that are similar,
but not identical to, those caused by Tsc2 mutation in mice. Natl.
Acad. Sci. U.S.A., 2001, 98, 8762-8767.
Kobayashi, T.; Hirayama, Y.; Kobayashi, E.; Kubo, Y.; Hino, O. A
germline insertion in the tuberous sclerosis (Tsc2) gene gives riseto the Eker rat model of dominantly inherited cancer. Nat. Genet.,
1995, 9, 70-74.
Mizuguchi, M.; Takashima, S.; Yamanouchi, H.; Nakazato, Y.;
Mitani, H.; Hino, O. Novel cerebral lesions in the Eker rat model ofYui et al.

[43]
[44]
[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]
[57]

[58]

[59]

tuberous sclerosis: cortical tuber and anaplastic ganglioglioma. J.
Neuropathol. Exp. Neurol., 2000, 59, 188-196.
Goorden, S.M.; van Woerden, G.M.; van der Weerd, L.; Cheadle,
J.P.: Elgersma, Y. Cognitive deficits in Tsc1+/- mice in the absenceof cerebral lesions and seizures. Ann. Neurol., 2007, 62, 648-655.
Waltereit, R.; Japs, B.; Schneider, M.; de Vries, P.J.; Bartsch, D.
Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social
deficit behaviors in rats. Behav. Genet., 2011, 41(3), 364-372.
Sato, A.; Kasai, S.; Kobayashi, T.; Takamatsu, Y.; Hino, O.; Ikeda,
K.; Mizuguchi, M. Rapamycin reverses impaired social interaction
in mouse models of tuberous sclerosis complex. Nat. Commun.,2012, 3, 1292.
Ehninger, D.; Han, S.; Shilyansky, C.; Zhou, Y.; L,i W.;
Kwiatkowski, D.J.; Ramesh, V.; Silva, A.J. Reversal of learning
deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat. Med.,2008, 14, 843-848.
Potter, W.B.; Basu, T.; O'Riordan, K.J.; Kirchner, A.; Rutecki, P.;
Burger, C.; Roopra, A. Reduced juvenile long-term depression in
tuberous sclerosis complex is mitigated in adults by compensatory
recruitment of mGluR5 and Erk signaling. PLoS Biol., 2013, 11(8),e1001627
Tsai, P.T.; Hull, C.; Chu, Y.; Greene-Colozzi, E.; Sadowski, A.R.;
Leech, J.M.; Steinberg, J.; Crawley, J.N.; Regehr, W.G.; Sahin, M.
Autistic-like behaviour and cerebellar dysfunction in Purkinje cell
Tsc1 mutant mice. Nature, 2012, 488, 647-651.
Zeng, L.H.; Rensing, N.R.; Zhan, B.; Gutmann, D.H.; Gambello,
M.J.; Wong, M. Tsc2 gene inactivation causes a more severe
epilepsy phenotype than Tsc1 inactivation in a mouse model oftuberous sclerosis complex. Hum. Mol. Genet., 2011, 20, 445-454.
Krueger, D.A.; Wilfong, A.A.; Holland-Bouley, K.; Anderson,
A.E.; Agricola, K.; Tudor, C.; Mays, M.; Lopez, C.M.; Kim, M.O.;
Franz, D.N. Everolimus treatment of refractory epilepsy intuberous sclerosis complex. Ann. Neurol., 2013, 74, 679-687.
Marsh, D.J.; Kum, J.B.; Lunetta, K.L.; Bennett, M.J.; Gorlin, R.J.;
Ahmed, S.F.; Bodurtha, J.; Crowe, C.; Curtis, M.A.; Dasouki, M.;
Dunn, T.; Feit, H.; Geraghty, M.T.; Graham, J.M.Jr.; Hodgson,
S.V.; Hunter, A.; Korf, B.R.; Manchester, D.; Miesfeldt, S.;
Murday, V.A.; Nathanson, K.L.; Parisi, M.; Pober, B.; Romano, C.;
Eng, C. PTEN mutation spectrum and genotype-phenotype
correlations in Bannayan-Riley-Ruvalcaba syndrome suggest asingle entity with Cowden syndrome. Hum. Mol. Genet., 1999, 8,
1461-1472.
Zhou, X.P.; Marsh, D.J.; Morrison, C.D.; Chaudhury, A.R.;
Maxwell, M.; Reifenberger, G.; Eng, C. Germline inactivation of
PTEN and dysregulation of the phosphoinositol-3-kinase/Aktpathway cause human Lhermitte-Duclos disease in adults. Am. J.
Hum. Genet., 2003, 73, 1191-1198.
Butler, M.G.; Dasouki, M.J.; Zhou, X.P.; Talebizadeh, Z.; Brown,
M.; Takahashi, T.N.; Miles, J.H.; Wang, C.H.; Stratton, R.;
Pilarski, R.; Eng, C. Subset of individuals with autism spectrum
disorders and extreme macrocephaly associated with germline
PTEN tumour suppressor gene mutations. J. Med. Genet., 2005, 42,318-321.
Varga, E.A.; Pastore, M.; Prior, T.; Herman, G.E.; McBride, K.L.
The prevalence of PTEN mutations in a clinical pediatric cohort
with autism spectrum disorders, developmental delay, andmacrocephaly. Genet. Med., 2009, 11, 111-117.
McBride, K.L.; Varga, E.A.; Pastore, M.T.; Prior, T.W.;
Manickam, K.; Atkin, J.F.; Herman, G.E. Confirmation study ofPTEN mutations among individuals with autism or developmental
delays/mental retardation and macrocephaly. Autism Res., 2010, 3,
137-41.
Di Cristofano, A.; Pesce, B.; Cordon-Cardo, C.; Pandolfi, P.P. Pten
is essential for embryonic development and tumour suppression.
Nat. Genet., 1998, 19, 348-355.
Page, D.T.; Kuti, O.J.; Prestia, C.; Sur, M. Haploinsufficiency for
Pten and Serotonin transporter cooperatively influences brain sizeand social behavior. Proc. Natl. Acad. Sci. U.S.A., 2009, 106, 19891994.
Kwon, C.H.; Luikart, B.W.; Powell, C.M.; Zhou, J.; Matheny,
S.A.; Zhang, W.; Li, Y.; Baker, S.J.; Parada, L.F. Pten regulates
neuronal arborization and social interaction in mice. Neuron, 2006,
50, 377-388.
Zhou, J.; Blundell, J.; Ogawa, S.; Kwon, C.H.; Zhang, W.; Sinton,
C.; Powell, C.M.; Parada, L.F. Pharmacological inhibition of

Mitochondrial Dysfunction and Its Relationship

[60]

[61]

[62]
[63]
[64]

[65]

[66]

[67]

[68]

[69]
[70]

[71]

[72]

[73]

[74]

[75]
[76]

[77]

mTORC1 suppresses anatomical, cellular, and behavioral
abnormalities in neural-specific Pten knock-out mice. J. Neurosci.,
2009, 29, 1773-1783.
Devys, D.; Lutz, Y.; Rouyer, N.; Bellocq, J.P.; Mandel, J.L. The
FMR-1 protein is cytoplasmic, most abundant in neurons andappears normal in carriers of a fragile X premutation. Nat. Genet.,
1993, 4, 335-340.
Tranfaglia, M.R. The psychiatric presentation of fragile x:
evolution of the diagnosis and treatment of the psychiatriccomorbidities of fragile X syndrome. Dev. Neurosci., 2011, 33,
337-348.
Bear, M.F.; Huber, K.M.; Warren, S.T. The mGluR theory offragile X mental retardation. Trends Neurosci., 2004, 27, 370-377.
Dölen, G.; Osterweil, E.; Rao, B.S.; Smith, G.B.; Auerbach, B.D.;
Chattarji, S.; Bear, M.F. Correction of fragile X syndrome in mice.
Neuron, 2007, 56, 955-962.
Sharma, A.; Hoeffer, C.A.; Takayasu, Y.; Miyawaki, T.; McBride,
S.M.; Klann, E.; Zukin, R.S. Dysregulation of mTOR signaling infragile X syndrome in fragile X syndrome. J. Neurosci., 2010, 30,
694-702.
Bhattacharya, A.; Kaphzan, H.; Alvarez-Dieppa, A.C.; Murphy,
J.P.; Pierre, P.; Klann, E. Genetic removal of p70 S6 kinase 1
corrects molecular, synaptic, and behavioral phenotypes in fragile
X syndrome mice. Neuron, 2012, 76, 325-337.
Viskochil, D.; Buchberg, A.M.; Xu, G.; Cawthon, R.M.; Stevens,
J.; Wolff, R.K.; Culver, M.; Carey, J.C.; Copeland, N.G.; Jenkins,
N.A. Deletions and a translocation interrupt a cloned gene at theneurofibromatosis type 1 locus. Cell, 1990, 62, 187-192.
Cawthon, R.M.; Weiss, R.; Xu, G.F.; Viskochil, D.; Culver, M.;
Stevens, J.; Robertson, M.; Dunn, D.; Gesteland, R.; O'Connell, P.
A major segment of the neurofibromatosis type 1 gene: cDNA
sequence, genomic structure, and point mutations. Cell, 1990, 62,
193-201.
Wallace, M.R; Marchuk, D.A.; Andersen, L.B.; Letcher, R.; Odeh,
H.M.; Saulino, A.M.; Fountain, J.W.; Brereton, A.; Nicholson, J.;
Mitchell, A.L. Type 1 neurofibromatosis gene: identification of alarge transcript disrupted in three NF1 patients. Science, 1990, 249,
181-186.
Hyman, S.L.; Shores, A.; North, K.N. The nature and frequency ofcognitive deficits in children with neurofibromatosis type 1.
Neurology, 2005, 65, 1037-1044.
Costa, R.M.; Federov, N.B.; Kogan, J.H.; Murph, G.G.; Stern, J.;
Ohno, M.; Kucherlapati, R.; Jacks, T.; Silva, A.J. Mechanism forthe learning deficits in a mouse model of neurofibromatosis type 1.
Nature, 2002, 415, 526-30.
Donovan, S.; See, W.; Bonifas, J.; Stokoe, D.; Shannon, K.M.
Hyperactivation of protein kinase B and ERK have discrete effects
on survival, proliferation, and cytokine expression in Nf1-deficient
myeloid cells. Cancer Cell, 2002, 2, 507-514.
Johannessen, C.M.; Reczek, E.E.; James, M.F.; Brems, H.; Legius,E.; Cichowski, K. The NF1 tumor suppressor critically regulates
TSC2 and mTOR. Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 85738578.
Li, W.; Cui, Y.; Kushner, S.A.; Brown, R.A.; Jentsch, J.D.;
Frankland, P.W.; Cannon, T.D.; Silva, A.J. The HMG-CoA
reductase inhibitor lovastatin reverses the learning and attention
deficits in a mouse model of neurofibromatosis type 1. Curr. Biol.,
2005, 15, 1961-1967.
Krab, L.C.; de Goede-Bolder, A.; Aarsen, F.K.; Pluijm, S.M.;
Bouman, M.J.; van der Geest, J.N.; Lequin, M.; Catsman, C.E.;
Arts, W.F.; Kushner, S.A.; Silva, A.J.; de Zeeuw, C.I.; Moll, H.A.;
Elgersma, Y. Effect of simvastatin on cognitive functioning inchildren with neurofibromatosis type 1: a randomized controlled
trial. J.A.M.A., 2008, 300, 287-294.
Mbarek, O.; Marouillat, S.; Martineau, J.; Barthélémy, C.; Müh,
J.P.; Andres, C. Association study of the NF1 gene and autistic
disorder. Am. J. Med. Genet., 1999, 88, 729-732.
Walsh, K.S.; Vélez, J.I.; Kardel, P.G.; Imas, D.M.; Muenke, M.;
Packer, R.J.; Castellanos, F.X.; Acosta, M.T. Symptomatology ofautism spectrum disorder in a population with neurofibromatosis
type 1. Dev. Med. Child Neurol., 2013, 55, 131-138.
Garg, S.; Lehtonen, A.; Huson, S.M.; Emsley, R.; Trump, D.;
Evans, D.G.; Green, J. Autism and other psychiatric comorbidity inneurofibromatosis type 1: evidence from a population-based study.
Dev. Med. Child Neurol., 2013, 55, 139-145.

Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5
[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]
[86]

[87]

[88]
[89]
[90]
[91]

[92]

[93]

[94]
[95]

15

Molosh, A.I.; Johnson, P.L.; Spence, J.P.; Arendt, D.; Federici,
L.M.; Bernabe, C.; Janasik, S.P.; Segu, Z.M.; Khanna, R.;
Goswami, C.; Zhu, W.; Park, S.J.; Li, L.; Mechref, Y.S.; Clapp,
D.W.; Shekhar, A. Social learning and amygdala disruptions in Nf1
mice are rescued by blocking p21-activated kinase. Nat. Neurosci.,
2014, doi: 10.1038/nn.3822. [Epub ahead of print]
Antion, M.D.; Merhav, M.; Hoeffer, C.A.; Reis, G.; Kozma, S.C.;
Thomas, G.; Schuman, E.M.; Rosenblum, K.; Klann, E. Removalof S6K1 and S6K2 leads to divergent alterations in learning,memory, and synaptic plasticity. Learn. Mem., 2008, 15, 29-38.
Pause, A.; Belsham, G.J.; Gingras, A.C.; Donzé, O.; Lin, T.A.;
Lawrence, J.C.Jr.; Sonenberg, N. Insulin-dependent stimulation ofprotein synthesis by phosphorylation of a regulator of 5'-capfunction. Nature. 1994, 371,762-767.
Gingras, A.C.; Raught, B.; Gygi, S.P.; Niedzwiecka, A.; Miron,M.; Burley, S.K.; Polakiewicz, R.D.; Wyslouch-Cieszynska, A.;
Aebersold, R.; Sonenberg, N. Hierarchical phosphorylation of thetranslation inhibitor 4E- BP1. Genes. Dev., 2001, 15, 2852-2864.
Moerke, N.J.; Aktas, H.; Chen, H.; Cantel, S.; Reibarkh, M.Y.;
Fahmy, A.; Gross, J.D.; Degterev, A.; Yuan, J.; Chorev, M.;
Halperin, J.A.; Wagner, G. Small-molecule inhibition of theinteraction between the translation initiation factors eIF4E andeIF4G. Cell, 2007, 128, 257-267.
Gkogkas, C.G.; Khoutorsky, A.; Ran, I.; Rampakakis, E.; Nevarko,
T.; Weatherill, D.B.; Vasuta, C.; Yee, S.; Truitt, M.; Dallaire, P.;
Major, F.; Lasko, P.; Ruggero, D.; Nader, K.; Lacaille, J.C.;
Sonenberg, N. Autism-related deficits via dysregulated eIF4Edependent translational control. Nature, 2013, 493, 371-377.
Santini, E.; Huynh, T.N.; MacAskill, A.F.; Carter, A.G.; Pierre, P.;
Ruggero, D.; Kaphzan, H.; Klann, E. Exaggerated translation
causes synaptic and behavioural aberrations associated with autism.
Nature, 2013, 493, 411-415.
Auerbach, B.D.; Osterweil, E.K.; Bear, M.F. Mutations causing
syndromic autism define an axis of synaptic pathophysiology.
Nature, 2011, 480, 63-68.
Moy, S.S.; Nadler, J.J.; Young, N.B.; Perez, A.; Holloway, L.P.;
Barbaro, R.P.; Barbaro, J.R.; Wilson, L.M.; Threadgill, D.W.;
Lauder, J.M.; Magnuson, T.R.; Crawley, J.N. Mouse behavioral
tasks relevant to autism: phenotypes of 10 inbred strains. Behav.
Brain Res., 2007, 176, 4-20.
Silverman, J.L.; Smith, D.G.; Rizzo, S.J.; Karras, M.N.; Turner,
S.M.; Tolu, S.S.; Bryce, D.K.; Smith, D.L.; Fonseca, K.; Ring,
R.H.; Crawley, J.N. Negative allosteric modulation of the mGluR5
receptor reduces repetitive behaviors and rescues social deficits inmouse models of autism. Sci. Transl. Med., 2012, 4, 131ra51.
Burket, J.A.; Benson, A.D.; Tang, A.H.; Deutsch, S.I. Rapamycin
improves sociability in the BTBR T(+)Itpr3(tf)/J mouse model ofautism spectrum disorders. Brain Res. Bull., 2014, 100, 70-75.
Chugani, D.C.; Sundram, B.S.; Behen, M.; Lee, M.L.; Moor, G.J.
Evidence of altered energy metabolism in autistic children. Prog.
Neuropsychopharmacol. Biol. Psychiatry, 1999, 23, 635-641
Al-Mosalem, O.A.; El-Ansary, A.; Attas, O.; Al-Ayadhi, L.
Metabolic biomarkers related to energy metabolism in Saudi
autistic children. Clin. Biochem., 2009, 42, 949-957.
Chauhan, A.; Gu, F.; Essa, M.M.; Wegiel, J.; Kaur, K.; Brown,
W.T.; Chauhan, V. Brain region-specific deficit in mitochondrial
electron transport chain complexes in children with autism. J.
Neurochem., 2011, 117, 209-220.
Tang, G.; Gudsnuk, K.; Kuo, S.H.; Cotrina, M.L.; Rosoklija, G.;
Sosunov, A.; Sonders, M.S.; Kanter, E.; Castagna, C.; Yamamoto,A.; Yue, Z.; Arancio. O.; Peterson, B.S.; Champagne, F.; Dwork,
A.J.; Goldman, J.; Sulzer, D. Loss of mTOR-dependent
macroautophagy causes autistic-like synsptic pruning deficit.
Neuron, 2014, 83(5), 1131-1143.
Schieke, S.M.; Phillips, D.; McCoy, J.P. Jr.; Aponte, A.M.; Shen,
R.F.; Balaban, R.S.; Finkel, T. The mammalian target of rapamycin(mTOR) pathway regulates mitochondrial oxygen consumption andoxidative capacity. J. Biol. Chem., 2006, 281(37), 27643-27652.
Goo, C.K.; Lim, H.Y.; Ho, Q.S.; Too, H.P.; Clement, M.V.; Wong,
K.P. PTEN/Akt signaling controls mitochondrial respiratory
capacity through 4E-BP1. PLoS One, 2012, 7(9), e45806.
Di Nardo, A.; Kramvis, I.; Cho, N.; Sadowski, A.; Meikle, L.;
Kwiatkowski, D.J.; Sahin, M. Tuberous sclerosis complex activity
is required to control neuronal stress responses in an mTORdependent manner. J. Neurosci., 2009, 29, 5926-5937.

16 Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5
[96]

[97]

[98]
[99]

[100]

[101]

[102]

[103]

[104]

[105]

[106]

[107]
[108]

[109]
[110]
[111]
[112]

[113]
[114]

James, S.J.; Rose, S.; Melnyk, S.; Jernigan, S.; Blossom, S.; Pavliv,
O.; Gaylor, D.W. Cellular and mitochondrial glutathione redox
imbalance in lymphoblastoid cells derived from children with
autism. F.A.S.E.B. J., 2009, 23, 2374-2383.
Ozcan, U.; Ozcan, L.; Yilmaz, E.; Düvel, K.; Sahin, M.; Manning,
B.D.; Hotamisligil, G.S. Loss of the tuberous sclerosis complex
tumor suppressors triggers the unfolded protein response toregulate insulin signaling and apoptosis. Mol. Cell, 2008, 29, 541551.
Haas, R.H.; Parikh, S.; Falk, M.J.; Saneto, R.P.; Wolf, N.I.; Darin,N.; Cohen, B.H. Mitochondrial disease: a practical approach forprimary care physicians. Pediatrics, 2007, 120(6), 1326-1233.
Goh, S.; Dong, Z.; Zhang, Y.; DiMauro, S.; Peterson, B.S.
Mitochondrial dysfunction as a neurobiological subtype of autism
spectrum disorder: evidence from brain imaging. J.A.M.A.
Psychiatry, 2014, 71(6), 665-671.
Weissman, J.R.; Kelley, R.I.; Bauman, M.L.; Cohen, B.H.; Murray
K.F.; Mitchel, R.L.; Kern, R.L.; Natowicz, M.R. Mitochondrial
disease in autism spectrum disorder patients: a cohort analysis.
PLos One, 2008, 3(11), e3815.
Frye, R.E.; Delatorre, R.; Taylor, H.; Slattery, J.; Melnyk, S.;
Chowdhury, N.; James, S.J. Redox metabolism abnormalities in
autistic children associated with mitochondrial disease. Transl.
Psychiatry, 2013, 3, e273.
Yorbik, O.; Sayal, A.; Akay, C.; Akbiyi, DI.; Sohmen, T.
Investigation of antioxidant enzymes in children with autistic
disorder. Prostagland. Leukot. Essent. Fatty Acids, 2002, 67: 341343.
Sögüt, S.; Zoroğlu, SS.; Özyurt, H.; Yilmaz, H.R.; Özugurlu, F.;
Sivasli, E.; Yetkin, O.; Yanik, M.; Tutkun, H.; Savaş, H.A.;
Tarakçioğlu, M.; Akyol, O. Changes in nitric oxide levels andantioxidant enzyme activities may hay a role in thepathophysiolgical mechanisms involved in autism. Clin. Chim.
Acta, 2006, 331: 111-117.
Zoroglu, S.S.; Armutcu, F.; Ozen, S.; Gurel, A.; Sivasli, E.; Sivasli,
E.; Yetkin, O.; Meram, I. Increased oxidative stress and alteredactivities of erythrocyte free radical scavenging enzymes in autism.
Eur. Arch. Psychiatry Clin. Neurosci., 2004, 254, 143-147.
Meguid, N.; Dardir, A.A.; Abdel-Raouf E.R.; Hashish, A.
Evaluation of oxidative stress in autism: defective antioxidant
enzymes and increased lipid peroxidation. Biol. Trace Elem. Res.,
2011, 143, 58-65.
Parellada, M.; Moreno, C.; Mac-Dowell, K.; Leza, J.C.; Giraldez,
M.; Bailón, C.; Castro, C.; Miranda-Azpiazu, P.; Fraguas, D.;
Arang, C. Plasma antioxidant capacity is reduced in Asperger
syndrome. J. Psychiat. Res., 2012, 46, 394-401.
Lü, J.M.; Lin, P.H.; Yao, Q.; Chen, C. Chemical and molecularmechanisms of antioxidants: experimental approaches and model
systems. J. Cell Mol. Med., 2010, 14(4), 840-860.
Hartman, M.L.; Shirihai, O.S.; Holbrook, M.; Xu, G.; Kocherla,
M.; Shah, A. Relation of mitochondrial oxygen consumption in
peripheral blood mononuclear cells to vascular function in type 2
diabetes mellitus. Vasc. Med., 2014, 19(1), 67-74.
Kusano, C.; Ferrari, B.; Total antioxidant capacity: a biomarker inbiomedical and nutritional studies. J. Cell Mol. Biol., 2008, 7(1): 115.
Niki, E. Do antioxidants impair signaling by reactive oxygen
species and lipid oxidation products? FEBS Lett., 2012, 586(21),3767-3770.
Ribas, V.; García-Ruiz, C.; Fernández-Checa, JC. Glutathione andmitochondria. Front. Pharmacol., 2014, 5, 151. doi: 10.3389/
fphar.2014.00151.
Dunning, S.; Ur Rehman, A.; Tiebosch, M.H.; Hannivoort, R.A.;
Haijer, F.W.; Woudenberg, J.; van den Heuvel, FA.; Buist-Homan,M.; Faber, K.N.; Moshage, H. Glutathione and antioxidant
enzymes serve complementary roles in protecting activated hepatic
stellate cells against hydrogen peroxide-induced cell death.
Biochim. Biophys. Acta, 2013, 1832(12), 2027-2034.
Franco, R.; Cidlowski, J.A. Apoptosis and glutathione: beyond anantioxidant. Cell Death Differ., 2009, 16(10), 1303-1314.
Greetham, D.; Grant, C.M.; Antioxidant activity of the yeast
mitochondrial one-Cys peroxiredoxin is dependent on thioredoxin
reductase and glutathione in vivo. Mol. Cell Biol., 2009, 29(11),3229-3240.

Yui et al.
[115]
[116]

[117]
[118]

[119]
[120]
[121]
[122]

[123]

[124]
[125]

[126]
[127]

[128]

[129]
[130]

[131]
[132]

[133]

[134]

Dröse, S.; Brandt, U.; Wittig, I. Mitochondrial respiratory chain
complexes as sources and targets of thiol-based redox-regulation.
Biochim. Biophys. Acta, 2014, 1844(8), 1344-1354.
Koopman, W.J.; Nijtmans, L.G.; Dieteren, C.E.; Roestenberg, P.;
Valsecchi, F.; Smeitink, .JA.; Willems, P.H. Mammalian
mitochondrial complex I: biogenesis, regulation, and reactive
oxygen species generation. Antioxid. Redox Signal., 2010, 12(12),1431-1470.
Sorrentino, G.; Comel, A.; Mantovani, F.; Del Sal, G. Regulation of
mitochondrial apoptosis by Pin1 in cancer and neurodegeneration.
Mitochondrion, 2014, Pt A:88-96. doi: 10.1016/j.mito.2014.08.003.
Ghanizadeh, A.; Berk, M.; Farrashbandi, H.; Alavi Shoushtari, A.;
Villagonzalo, K.A. Targeting the mitochondrial electron transport
chain in autism, a systematic review and synthesis of a novel
therapeutic approach. Mitochondrion, 2013, 13(5), 515-519.
Naviaux, R.K. Oxidative shielding or oxidative stress? J.
Pharmacol. Exp. Ther., 2012, 342(3), 608-618.
Nicolson, G.L. Mitochondrial dysfunction and chronic disease:treatment with natural supplements. Altern. Ther. Health Med.,
2014, Suppl 1, 18-25.
Mattman, A.; Sirrs, S.; Mezei, M.M.; Salvarinova-Zivkovic, R.;
Alfadhel, M.; Lillquist, Y. Mitochondrial disease clinicalmanifestations: An overview. B.C.M. J., 2011, 53(4), 183-187.
Correia, C.; Coutinho, A.M.; Diogo, L.; Grazina, M.; Marques, C.;
Miguel, T.; Ataíde, A.; Almeida, J.; Borges, L.; Oliveira, C.;
Oliveira, G.; Vicente, A.M. Brief report: High frequency ofbiochemical markers for mitochondrial dysfunction in autism: no
association with the mitochondrial aspartate/glutamate carrier
SLC25A12 gene. J. Autism Dev. Disord., 2006, 36(8), 1137-1140.
Oliveira, G.; Diogo, L.; Grazina, M.; Garcia, P.; Ataíde, A.;
Marques, C.; Miguel, T.; Borges, L.; Vicente, A.M.; Oliveira, C.R.
Mitochondrial dysfunction in autism spectrum disorders: a
population-based study. Dev. Med. Child Neurol., 2005, 47(3),185-189.
Chinnery, P.F.; Elliott, H.R.; Hudson, G.; Samuels, D.C.; Relton,
C.L. Epigenetics, epidemiology and mitochondrial DNA diseases.
Int. J. Epidemiol., 2012, 41(1), 177-187.
Shoffner, J.; Hyams, L.; Langley, G.N.; Cossette, S.; Mylacraine,L.; Dale, J.; Ollis, L.; Kuoch, S.; Bennett, K.; Aliberti, A.; Hyland,
K. Fever plus mitochondrial disease could be risk factors for
autistic regression. J. Child. Neurol., 2010, 25(4), 429-434.
Palmieri, L.; Persico, A.M. Mitochondrial dysfunction in autism
spectrum disorders: cause or effect? Biochim. Biophys. Acta, 2010,
1797(6-7), 1130-1137.
Essa, M.M.; Guillemin, G.J.; Waly, M.I.; Al-Sharbati, M.M.; AlFarsi, Y.M.; Hakkim, F.L.; Ali, A.; Al Shafaee, M.S. Increased
markers of oxidative stress in autistic children of the Sultanate of
Oman. Biol. Trace Elem. Res., 2012, 147(1-3), 25-27.
Rossignol, D.A.; Frye, R.E. Evidence linking oxidative stress,
mitochondrial dysfunction, and inflammation in the brain ofindividuals with autism. Front. Physiol., 2014, 150, doi:
10.3389/fphys.2014.00150.
Lemire, J.; Auger, C.; Mailloux, R.; Appanna, V.D. Mitochondrial
lactate metabolism is involved in antioxidative defense in humanastrocytoma cells. J. Neurosci. Res., 2014, 92(4), 464-75.
Vanni, S.; Socci, F.; Pepe, G.; Nazerian, P.; Viviani, G.; Baioni,
M.; Conti, A.; Grifoni, S. High plasma lactate levels are associatedwith increased risk of in-hospital mortality in patients withpulmonary embolism. Acad. Emerg. Med., 2011, 18(8), 830-835.
Schell, J.C.; Rutter, J. The long and winding road to themitochondrial pyruvate carrier. Cancer Metab., 2013, 1(1), 6.
Nielsen, T.H.; Olsen, N.V.; Toft, P.; Nordström, C.H.; Cerebral
energy metabolism during mitochondrial dysfunction induced bycyanide in piglets. Acta Anaesthesiol. Scand., 2013, 57(6), 793801.
Lowes, D.A;, Webster, N.R.; Murphy, M.P.; Galley, H.F.;
Antioxidants that protect mitochondria reduce interleukin-6 andoxidative stress, improve mitochondrial function, and reduce
biochemical markers of organ dysfunction in a rat model of acutesepsis. Br. J. Anaesth., 2013, 110(3), 472-480.
Sadli, N.; Barrow, C. J.; McGee, S.; Suphioglu, C.; Effect of DHA
and coenzymeQ10 against Aβ- and zinc-induced mitochondrial
dysfunction in human neuronal cells. Cell Physiol. Biochem., 2013,32(2), 243-252.

Mitochondrial Dysfunction and Its Relationship
[135]

[136]

[137]
[138]

[139]

[140]

[141]

[142]

[143]

[144]

Mini-Reviews in Medicinal Chemistry, 2015, Vol. 15, No. 5

Sandhir, R.; Mehrotra, A.; Quercetin supplementation is effectivein improving mitochondrial dysfunctions induced by 3nitropropionic acid: implications in Huntington's disease. Biochim.
Biophys. Acta, 2013, 1832(3), 421-430.
Ferretta, A.; Gaballo, A.; Tanzarella, P.; Piccoli, C.; Capitanio, N.;
Nico, B.; Annese, T., Di Paola, M.; Dell'aquila, C.; De Mari, M.;
Ferranini, E.; Bonifati, V.; Pacelli, C.; Cocco, T. Effect ofresveratrol on mitochondrial function: implications in parkinassociated familiar Parkinson's disease. Biochim. Biophys. Acta,
2014, 1842(7), 902-915.
Wu, G.; Fang, Y.Z.; Yang, S.; Lupton, J.R.; Turner, N.D.
Glutathione metabolism and its implications for health. J. Nutr.,
2004, 134(3), 489-492.
Main, P.A.; Angley, M.T.; O'Doherty, C.E.; Thomas, P.; Fenech,
M. The potential role of the antioxidant and detoxification
properties of glutathione in autism spectrum disorders: a systematic
review and meta-analysis. Nutr. Metab (London)., 2012, 9,35. doi:
10.1186/1743-7075-9-3.
James, S. J.; Rose, S.; Melnyk, S.; Jernigan,S.; Blossom,S.; Pavliv,
O.; Gaylor, D.W.. Cellular and mitochondrial glutathione redox
imbalance in lymphoblastoid cells derived from children with
autism. F.A.S.E.B.J., 2009, 23(8): 2374-2383.
Gu, F.; Chauhan, V.; Chauhan, A. Impaired synthesis andantioxidant defense of glutathione in the cerebellum of autistic
subjects: alterations in the activities and protein expression of
glutathione-related enzymes. Free Radic. Biol. Med., 2013, 65,
488-496.
Rose, S.; Melnyk, S.; Pavliv, O.; Bai, S; Nick, T.G.; Frye, R.E.;
James, S.J. Evidence of oxidative damage and inflammation
associated with low glutathione redox status in the autism brain.
Transl. Psychiatry, 2012, 2:e134. doi: 10.1038/tp.2012.61.
Frye, R.E.; Melnyk, S.; Fuchs, G.; Reid, T.; Jernigan, S.; Pavliv,
O.; Hubanks, A.; Gaylor, D.W.; Walters, L.; James, S.J.
Effectiveness of methylcobalamin and folinic Acid treatment on
adaptive behavior in children with autistic disorder is related to
glutathione redox status. Autism Res. Treat., 2013, 609705.
James, S.J.; Cutler, P.; Melnyk, S.; Jernigan, S.; Janak, L.; Gaylor,
D.W.; Neubrander, J.A. Metabolic biomarkers of increasedoxidative stress and impaired methylation capacity in children with
autism. Am. J. Clin. Nutr., 2004, 80(6), 1611-1617.
James, S.J.; Melnyk, S.; Fuchs, G.; Reid, T.; Jernigan S. Pavliv, O.;
Hubanks, A.; Gaylor, D.W. Efficacy of methylcobalamin andfolinic acid treatment on glutathione redox status in children with
autism. Am. J. Clin. Nutr., 2009, 89(1), 425-430.

Received: ?????????, 2014

[145]
[146]
[147]
[148]

[149]
[150]
[151]

[152]

[153]
[154]

[155]

[156]
[157]
[158]

17

Alabdali, A.; Al-Ayadhi, L.; El-Ansary, A. key role for an impaired
detoxification mechanism in the etiology and severity of autism
spectrum disorders. B.B.F., 2014, 10, 14.
Mazefsky, C. A.; McPartland, J. C.; Gastgeb, H. Z.; Minshew, N. J.
Brief report: comparability of DSM-IV and DSM-5 ASD researchsamples. J. Autism Dev. Disord., 2013, 43(5), 1236-1242.
Frye, R.E.; James, S.J. Metabolic pathology of autism in relation toredox metabolism. Biomark. Med., 2014, 8(3), 321-330.
Jheng, H.F.; Tsai, P.J.; Guo, S.M.; Kuo, L.H.; Chang, C.S.; Su, I.J.;
Chang, C.R.; Tsai, Y.S. Mitochondrial fission contributes tomitochondrial dysfunction and insulin resistance in skeletal muscle.
Mol. Cell Biol., 2012, 32(2), 309-319.
Kim, J.A.; Wei, Y.; Sowers, J.R. Role of mitochondrial dysfunction
in insulin resistance. Circ. Res., 2008, 102(4), 401-414.
Lu, S.C. Regulation of glutathione synthesis. Mol. Aspects Med.,2009, 30(1-2), 42-59.
Chauhan, A.; Chauhan, V.; Brown, WT.; Cohen, I. Oxidative stressin autism: increased lipid peroxidation and reduced serum levels of
ceruloplasmin and transferrin-the antioxidant proteins. Life Sci.,
2004, 75, 2539-2549.
Tórsdóttir, G.; Hreidarsson, S.; Kristinsson, J.; Snaedal, J.;
Jóhannesson, T. Ceruloplasmin, superoxide dismutase and copperin autistic patients. Basic Clin. Pharmacol. Toxicol., 2005, 96, 146148.
Lauritsen, M.B. Autism spectrum disorders. Eur. Child Adolesc.
Psychiatry, 2013, Suppl 1, S37-42.
Kotan, V.O.; Sarandol, E.; Kirhan, E.; Ozkaya, G.; Kirli, S. Effectsof long-term antidepressant treatment on oxidative status in major
depressive disorder: a 24-week follow-up study. Prog.
Neuropsychopharmacol. Biol. Psychiatry, 2011, 35(5), 1284-1290.
Anes A.B.; Fetoui, H.; Bchir, S.; ben Nasr, H.; Chahdoura, H.;
Chabchoub, E.; Yacoub, S.; Garrouch, A.; Benzarti, M.; Tabka, Z.;
Chahed, K. Increased oxidative stress and altered levels of nitricoxide and peroxynitrite in tunisian patients with chronic obstructive
pulmonary disease: correlation with disease severity and airflow
obstruction. Biol. Trace Elem. Res., 2014, 161(1), 20-31.
Damodaran, L.P.; Arumugam, G. Urinary oxidative stress markers
in children with autism. Redox Rep., 2011, 16(5), 216-222.
Ranjbar, A.; Rashedi, V.; Rezaei, M. Comparison of urinaryoxidative biomarkers in Iranian children with autism. Res. Dev.
Disa., 2014, 35(11), 2751-2755. doi: 10.1016/j.ridd.2014.07.010.
Rai, K.; Hegde, A.M.; Jose, N. Salivary antioxidants and oral
health in children with autism. Arch. Oral Biol., 2012, 57(8), 111611.

Revised: ?????????, 2014

Accepted: ?????????, 2014