Current Medicinal Chemistry, 2011, 18, 4715-4721 4715

Mitochondrial Alterations and Neuropsychiatric Disorders

D. Marazziti, S. Baroni, M. Picchetti, P. Landi, S. Silvestri, E. Vatteroni and M. Catena Dell’Osso

Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, Italy

Abstract: Mitochondria are membrane-enclosed organelle found in most eukaryotic cells, where they generate the majority of the cell’s
supply of adenosine triphosphate (ATP), used as a source of chemical energy. In addition, they are involved in a range of other processes,
such as signalling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. Mitochondria have been
implicated in several neuropsychiatric disorders, in particular, depression, anxiety, schizophrenia, autism, and Alzheimer’s dementia.
Furthermore, the presence of mutations at the level of mitochondrial or nuclear DNA (mtDNA and nDNA, respectively) has been linked
to personality disorders, behavioral disturbances, thought alterations, impulsivity, learning impairment, cognitive failures until dementia.
The aim of this paper is to review the literature on the relationship between psychiatric symptoms or syndromes and mtDNA mutations or
mitochondrial alterations, while highlighting novel therapeutic targets for a broad range of disorders.
Keywords: Mitochondria, ATP, Genetics, Mitochondrial Diseases, Schizophrenia, Mood Disorders, Anxiety Disorders, Autism, ADHD,
Alzheimer’s disease.

INTRODUCTION The mitochondrial respiratory chain is associated with the inner

Mitochondria are intracellular organelles responsible for the
production of adenosine triphosphate (ATP), a high-energy
compound utilized for most of the metabolic processes of the cells
and exchanged with adenosine diphosphate (ADP) in the cytosol.
The story of the mitochondria began in 1890 when Altman first
discovered the presence of granular structures within the cell and
concluded that they were "elementary bodies engaged in vital
functions [1]. The name mitochondria was derived from the Greek
word "mythos" (wire) and "chondros"(small grain) and was
employed for the first time in 1898 by Benda [2]. In 1913 Warburg
observed that cellular respiration in liver extracts was linked to
particles and in 1937 that these were related to the cytochromes of
the respiratory chain [3]. Subsequently, oxidative phosphorylation
was shown to occur within the mitochondria [4, 5]. A few years
later, with the advent of the high-resolution electron microscopy, it
was demonstrated that the double folded membrane of the
mitochondria was essential for phosphorylation processes [6].
Mithocondria are composed by several compartments, each of
them subserving different functions. The mitochondrial outer
membrane encloses the entire organelle and contains porin proteins
that serve as diffusion channels for minute molecules across the
membrane. The folded mitochondrial inner membrane contains
about 1/5 of the mitochondrial proteins, but has no porin proteins
and includes several hundred polypeptides. This membrane is
impermeable so that ions and molecules require special membrane
transporters to pass through it. The inner membrane folds are
known as cristae: with their folds, the cristae increase the total
surface area of the inner membrane enhancing its ability to produce
ATP. The space between the outer membrane and the inner
membrane is called intermembrane space, while the matrix is the
space enclosed by the inner membrane. The ATP is produced in the
matrix by the ATP synthase present in the inner membrane. The
matrix also contains a highly-concentrated mixture of hundreds of
enzymes, special mitochondrial ribosomes, transfer ribonucleic acid
(tRNA), and several copies of the mitochondrial deoxyribonucleic
acid (DNA) genome.
Mitochondria possess their own DNA called mitochondrial
DNA (mtDNA), a small circular molecule of 16.5 kb containing 37
genes for two ribosomal RNA (rRNA), 22 tRNAs and 13 proteins
that are part of the enzymatic complex assigned to the oxidative
phosphorylation. Most of the genes encoding mitochondrial
proteins are contained in the nuclear DNA (nDNA).
*Address correspondence to this author at the Dipartimento di Psichiatria,
Neurobiologia, Farmacologia e Biotecnologie, University of Pisa, via Roma, 67,
I-56100 Pisa, Italy; Tel: +39 050 2219768; Fax: +39 050 2219787;
E-mail: dmarazzi@psico.med.unipi.it
mitochondrial membrane and consists of several protein complexes
that form the mitochondrial electron transport system. The
respiratory chain complexes transfer electrons from an electron
donor to an electron acceptor and are associated with a proton pump
to create a transmembrane electrochemical gradient. The respiratory
chain consists of four multisubunit complexes (complexes I-IV)
that, together with complex V (ATP synthase), form the respiratory
chain/oxidative phosphorylation system. The first four complexes
act together to generate a proton gradient that is coupled to the
conversion of ADP and inorganic phosphate to ATP in complex V.
Complex I (NADH–ubiquinone oxidoreductase) is the major
entrance point of electrons to the respiratory chain. It has a
molecular mass of approximately 1 MDa and is composed by two
domains. One domain is localized within the inner mitochondrial
membrane and is involved in proton translocation; the other domain
protrudes out of the plain of the membrane into the mitochondrial
matrix and is responsible for oxidation of NADH [7]. Complex II
(succinate–ubiquinone oxidoreductase) is a second entrance point
of electrons to the respiratory chain and consists of two soluble
matrix-exposed subunits that are attached to two hydrophobic
membrane proteins [8,9].
Complex III (ubiquinol–cytochrome c oxidoreductase)
represents the central component of the mitochondrial oxidative
phosphorylation system [10]. About 1/4 of the complex is
embedded within the inner mitochondrial membrane, a small part
protrudes out into the mitochondrial intermembrane space and a
larger part protrudes into the mitochondrial matrix. Complex IV
(cytochrome c–O2 oxidoreductase) is the terminal complex of the
respiratory chain. It can exist as a monomer or a dimer within the
membrane [11]. The ATP synthase complex (complex V) is a
bipartite structure composed of a so-called F1 headpiece within the
mitochondrial matrix, which is anchored to a hydrophobic F0-part
within the inner mitochondrial membrane [12]. The two parts of
complex V are linked by a central stalk that rotates during catalysis
and by a peripheral stalk that prevents rotation of the entire
headpiece. The rotation of subunits within the two subcomplexes of
complex V is caused by the proton gradient across the inner
mitochondrial membrane and forms the basis for phosphorylation
of ADP.
As already mentioned, the pivotal role of the mitochondria is
the production of ATP, reduced nicotinamide adenine dinucleotide
(NADH) and reduced flavin adenine dinucleotide (FADH2). Briefly,
the pyruvate produced during the glycolysis easily enters the
mitochondria matrix where it undergoes further breakdown through
a process called aerobic respiration. This process requires oxygen
and yields much more energy than glycolysis. The aerobic
respiration is divided into two processes: the Krebs cycle, and the
electron transport chain. Prior to entering the Krebs cycle, pyruvate

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4716 Current Medicinal Chemistry, 2011 Vol. 18, No. 30
must be converted into acetyl coenzyme A (acetyl CoA) by
removing a CO2 molecule and then an electron to reduce an NAD +
into NADH. The acetyl group from acetyl CoA combines with
oxaloacetate forming citrate, which is converted into its isomer
isocitrate and oxidized to form the 5-carbon
-ketoglutarate. This
step releases one molecule of CO2 and reduces NAD+ to NADH2+.
The
-ketoglutarate is oxidized to succinyl CoA, yielding CO2 and
NADH2+. Succinyl CoA releases coenzyme A and phosphorylates
ADP into ATP. Succinate formed from this reaction is oxidized to
fumarate, converting FAD to FADH2, and fumarate is hydrolized to
form malate. Malate is then oxidized to oxaloacetate, reducing
NAD+ to NADH2+. For each molecule of glucose, six NADH2+, two
FADH2, and two ATP are formed. The NADH2+ and FADH 2
produced during the Krebs cycle transport the high energy electrons
and their accompanying hydrogen protons to the electron transport
chain in the inner mitochondrial membrane where ATP is produced
through chemiosmotic phosphorylation [13, 14, 15]. Other
mitochondrial functions include the control of the cell cycle,
signaling, differentiation, growth and death, the regulation of the
membrane potential, calcium signaling and steroid synthesis [16,
17,18,19]. A few indications are available that mitochondrial
dysfunctions may be present in psychiatric symptoms and/or
disorders. In this paper, therefore, we aimed at reporting a
comprehensive review of the evidence for mitochondrial
dysfunctions in different neuropsychiatric conditions.
GENETICS OF MITOCHONDRIAL DISEASES
The most common forms of mitochondrial diseases are those
due to respiratory chain defects. They are rare, sometimes difficult
to diagnose, often multisystemic and clinically heterogeneous. The
main symptoms are generally somatic, such as fatigue, weakness,
muscle pain, headache, tinnitus, hearing loss, visual changes,
ophthalmoplegia and diabetes mellitus; however, some psychiatric
symptoms, in particular, depression and suicidal ideation have been
also reported [20,21]. Mitochondrial diseases are characterized by
mtDNA mutations or mutations of nuclear genes encoding proteins
involved in the oxidative phosphorylation with consequent damage
of aerobic cell metabolism. The mtDNA is transmitted by maternal
inheritance and is not mendelian, since the mitochondria are
provided only by the egg cell. For this reason several mitochondrial
diseases are inherited by a matrilinear mode [22]. If there is a
mutation of the oocyte mtDNA, it is segregated randomly into
daughter cells, and a framework referred to as heteroplasmy
(coexistence of normal and mutated mtDNA) is the consequence,
with variable distribution of the mutated genes in subsequent cell
divisions and, therefore, in different tissues [23]. The opposite
condition is called homoplasy. Therefore, the phenotypic
expression depends on the quantity of mutated genomes in each
organ and on the dependence of each organ from oxidative
metabolism: the heart, brain and skeletal muscle tissues are the
most commonly organs affected by a mutation of mtDNA.
Although only mothers transmit the disease, according to the
mitochondrial genetic model, male and female subjects are equally
affected. In addition, the percentage of dizygotic and individuals
carrying a certain mutation in the offspring is very high, virtually
100%, but the percentage of mutated genomes transmitted to each
zygote and the subsequent tissue distribution are highly variable. As
a result, there is a heterogeneous phenotypic expression of the
genetic damage, even within the same family, from asymptomatic
carriers to patients with multisystemic syndromes. As mentioned
above, the mtDNA encodes only 13 structural proteins, all
belonging to the respiratory chain complexes, while the majority of
mitochondrial proteins are encoded by nDNA. A complex
interaction between the two genomes is thus at the basis of
mitochondrial protein synthesis and replication of mtDNA. This
dual genetic control implies that it is possible to distinguish three
groups of genetically-determined mitochondrial diseases: those
Marazziti et al.
associated with nDNA defects, those due to mtDNA defects and
those related to communication errors between the two genomes
[24].
MITOCHONDRIAL DISEASES
Patients with mitochondrial diseases have been classified in
different ways, according to clinical, histological and ultrastructural
alterations, or biochemical test of mitochondria functioning. In any
case, a few "specific" syndromes have been identified, in particular,
the Kearns Sayre syndrome (KSS), the chronic progressive external
ophthalmoplegia (CPEO), the Leber's hereditary optic neuropathy
(LHON), the mitochondrial myopathy, encephalopathy, lactic
acidosis, stroke-like episodes (cerebral infarction) (MELAS) and
myoclonic epilepsy with ragged red fibers (MERRF). However, it
was evident that there was a significant phenotypic difference
between patients with mitochondrial diseases that did not fit in any
of the specific syndromes [25]. Therefore, nowadays mitochondrial
diseases are more correctly divided into individual and familial, the
latter being transmitted through an autosomal dominant or recessive
matrilineal mode. In 1988, a point mutation at the ND4 subunit of
the complex I was described at the level of the mtDNA and was
related to the LHON [26]. Similarly, a deletion of the mtDNA was
shown to correlate with the KSS syndrome [27,28]. Up-to now,
more than 150 sites of mutation have been identified and a similar
number of rearrangements (partial deletions and duplications) of
mtDNA have been reported [23]. The majority of the human cells
contains two pairs of nDNA; however, the number of pairs of
mtDNA is larger (from 100 to 100,000) and more variable,
depending on the type of cell. The expression of at least 94% of the
16,569 base pairs of the double-stranded circular mtDNA is
required for the bioenergetic function of mitochondria, while only
7% of the nuclear genome, consisting of 109 base pairs, is expressed
[29]. The entire mtDNA is transmitted from the mother to all
children without recombination, so that they share the same
sequence of mtDNA, but may have different clinical
manifestations, due to the different proportion of mutated mtDNA
in the case of heteroplasmy. For example, a mutation in the cerebral
cortex may provoke a mental retardation or seizures, while a
mutation in the heart can cause a cardiomyopathy. This
phenomenon can occur even in identical twins with the
development of a partial CPEO in one of the two [30]. The
heteroplasmy explains only part of this phenomenon and nDNA
plays an important role, as shown by the large variability of
phenotypes expressed in the offspring of mothers who carry of
homoplasmic mutated mtDNA. Moreover, environmental factors
are supposed to play an important role in the expression of the
symptoms [31,32]. For example, in a case of identical twins, both
carrying a 3243A> G mutation, one of the two, who carried 50% of
mutated mtDNA in the blood, after a viral infection in the
childhood, developed a metabolic disorder which caused heart
failure and hypoxic-ischemic encephalopathy. On the contrary, the
other twin, who carried 90% of mutations, showed no intellectual
deficit or other symptoms [33].
MITOCHONDRIAL ALTERATIONS IN PSYCHIATRIC
DISORDERS
Over the past 20 years, there have been increasing observations
concerning the existence of a relationship between mitochondrial
dysfunctions and some psychiatric disorders. This kind of studies
used different techniques, such as analyses of portions of the
mitochondrial and nuclear genome or mRNA, proteins, ATP
production, and description of the ultrastructural mitochondria
features by electron microscopy in post-mortem brain tissue,
muscle or in blood cells.
According to some authors, psychotic, mood, anxiety and
personality disorders may be part of the clinical manifestations of
Mitochondrial Alterations and Neuropsychiatric Disorders
some mitochondrial diseases [34]. However, others are of the
opinion that psychiatric disorders would represent a complication of
the mitochondrial dysfunctions [20]. There are two interesting
studies exploring the psychiatric comorbidity in mothers of children
with mitochondrial diseases. In the first, carried out in 42 mothers,
more than 40% of them reported a pathological score on three
scales of the Minnesota Multiphasic Personality Inventory, in
particular hypochondria, hysteria and paranoia [35]. In the second,
some mothers of children with inherited mitochondrial disease
(MIMD) were compared with others who had children with
autosomal recessive metabolic disorders (ARMD) [25]. The results
showed that the total scores of the Beck Depression Inventory and
Beck Anxiety Inventory scales were three times higher in mothers
of children with MIMD, than in those with children affected by
ARMD. It was, therefore, important to determine whether the
scores of psychopathological scales previously mentioned were a
consequence of the particular situations of distress of the mothers,
who had to look after children with a severe disease with a poor
prognosis, or were due to mutations in the mitochondrial genome of
which they were carriers. To support the latter explanation, the
results showed that only two women who had adopted a child with
mitochondrial disease had MMPI-2 scores within the normal range.
SCHIZOPHRENIA
Scihzophrenia is a severe disorder characterized by different
symptoms, such as bizarre delusions, hallucinations (mainly
auditory), disorganized thinking, speech and behavior, social
withdrawl and a progressive impairment of global functioning. The
onset of schizophrenia typically occurs in the young adulthood,
with a prevalence of about 1%.
The pathophysiology of schizophrenia and related psychoses is
still unknown, but it is generally believed that it might result from
the interaction of genetic, environmental and neurobiological
factors. Recent data have suggested some possible correlation
between mithocondrial dysfunctions and schzophrenia. It is
interesting to note that the few studies exploring the mRNA
expression in the frontal cortex of schizophrenic patients, revealed
that the altered sequences were those encoding proteins of the
respiratory chain [36]. One heteroplasmic variant of the mtDNA,
encoding the ND4 subunits of the complex I, was also identified
and resulted to be more frequent in male schizophrenic patients
(47%) than in healthy control subjects (18%) [37].
A reduction of the complex IV and an age-dependent increase
of mtDNA deletions were observed in the frontal cortex and
caudate nucleus of treated schizophrenic patients, in contrast to
control subjects or patients with Alzheimer's dementia. However, it
is yet unclear whether the mitochondrial alterations are a primary or
secondary phenomenon of the main disorder [38]. Five new
variants of mtDNA, three of which located in the cytochrome b
gene have been recognized, although their association with
schizophrenia is to be yet clarified [39]. An increased activity of the
complex I was observed in platelets of schizophrenic patients with
or without antipsychotic treatment, but not in those patients
suffering from bipolar disorder (BD) or recurrent depression [40].
An increased activity of the complex II and IV in the putamen and a
reduction of the complex IV in the caudate nucleus have been
reported in psychotic patients under treatment [41]. In case of
relapse and chronic active disorder, high levels of the complex I
have been also described [42]. In patients treated with
antipsychotics, the flavoproteins subunits of 24 and 51 kDa showed
a reduction in their transcription and translation in the prefrontal
cortex, and the opposite in the visual association cortex [43]. A
reduction of the activity of the complex IV was observed in the
frontal cortex obtained postmortem from schizophrenic patients
treated with neuroleptics, while the complexes I, II, and IV were
altered in the temporal cortex, and complexes 1 and 3 in the basal
Current Medicinal Chemistry, 2011 Vol. 18, No. 30 4717
ganglia. However, no abnormality was found in the expression of
nuclear genes encoding proteins related to mitochondrial function
in the hippocampus [44]. The global down-regulation of genes
related to mitochondria found in the prefrontal cortex of
schizophrenic patients receiving neuroleptics, has been generally
interpreted as a secondary effect due to drug treatments [45]. It is
interesting to note that dopamine, a key neurotransmitter in
psychoses, may reduce ATP levels and inhibit the complex I, but
not complexes IV and V [46].
An increasing number of studies, carried out in peripheral CNS
models, would indicate that schizophrenic patients might be
characterized by a dysregulation in energy production by
mitochondria with a consequent increased oxidative stress that,
according to the opposite hypothesis, could be also the primary
event leading subsequently to mitochondrial alterations [47]. In
other words, damaged mitochondria would become less efficient
producers of ATP and more efficient producers of free radicals (and
the whole process would lead to a state of chronic oxidative stress)
[48] Further, mitochondria play an important role in maintaining
the homeostasis of calcium (Ca) that may trigger the cascade of
signals leading to cell apoptosis [49]. Taken together, these findings
would indicate that mitochondrial alterations may be involved in
some processes at the basis of different neurodegenerative
conditions, including schizophrenia, BD and Alzheimer’s disease
[47].
The possible role of mithocondria alterations in psychoses is
hence supported by scattered observations of isolated psychotic
symptoms, such as hallucinations, delusions and progressive
cognitive impairment, in some patients with mitochondrial diseases
characterized by a 3243A> G mutation and diagnosed by
hystochemical examination of muscle or enzymes [50-60].
MOOD DISORDERS
Mood disorder is a term designating a group of diagnoses in the
Diagnostic and Statistical Manual of Mental Disorders (DSM IV
TR) classification system where a disturbance in the individual’s
mood is hypothesized to be the main characteristic. Two groups of
mood disorders are widely recognized, based on whether the person
has ever had a manic or hypomanic episode. Therefore, there are
depressive disorders, of which the best known and most diagnosed
is major depressive disorder (MDD) and BD, characterized by
intermittent episodes of mania or hypomania, usually intervalled
with depressive episodes. The prevalence of mood disorders is
estimated to be 10%, up to 25 % during lifetime. Several patients
with mitochondrial diseases due to mtDNA mutations, including the
3243A> G mutation, may meet the criteria for a diagnosis of
unipolar depression and BD, and some of them may show psychotic
features and/or progressive cognitive deficits [52,61-72]. Genetic
studies have shown that major depression, probably transmitted by
mothers, is present in 51% of mothers of families affected by
mitochondrial diseases, as compared with 12% of mothers of
control subjects. Depression is also more frequent in maternal than
paternal grandmothers, in uncles and nephews, but only in the
group with apparent maternal transmission [73]. Data of these
studies suggest that changes in mtDNA sequence could favour the
development of depression. Moreover, a patients affected by the
familial form of CPEO was reported to suffer from recurrent
depressive episodes and other family members had mild depression
[74]. An association between BD and KSS has been also described
[75].
Some patients with both mitochondrial diseases and depression
may show peculiar alterations in the cerebral blood flow. In a
patient with an A343G mutation of mtDNA, depression, family
history of non-insulin dependent diabetes mellitus and cardiac
conduction disturbances, a reduction of the cerebral blood flow was
observed at the SPECT in the left globus pallidus, in the right
4718 Current Medicinal Chemistry, 2011 Vol. 18, No. 30
frontal and occipital lobes, after intravenous administration of I-
IMP. The patient was treated with coenzyme Q10 and idebenone
that led to a progressive improvement of depressive symptoms in a
few months [76]. A subsequent investigation showed an
improvement of blood flow in all the regions mentioned above. A
61 years-old man suffering from depression with an early onset and
a slowly developing multisystem syndrome including diabetes
mellitus, underwent SPECT after administration of Tc-HMPAO
and muscle biopsy to assess mitochondrial function. In this case a
reduction of blood flow was observed in the frontal and in the
inferior parietal lobes and an increase in the superior parietal lobe,
while the muscle biopsy revealed a reduction of the rate of
mitochondrial ATP production [77].
BIPOLAR DISORDER
Genetic studies showed a prevalence of women among first-
degree relatives of bipolar patients, while the transmission is
generally rare from male to male. Although these results were
initially correlated to a dominant X-linked transmission, no
alterations of the X chromosome were found, and this could be
explained only by a maternal transmission [78,79].
Mitochondrial dysfunctions in BD might be due to altered
expression of nuclear and mitochondrial genes encoding
mitochondrial proteins [80]. While using the technique of gene
arrays the expression of nuclear genes was evaluated in brain
samples, particularly the hippocampus of patients with BD,
schizophrenia and healthy control subjects: the results showed that
the expression of the nuclear mRNA encoding mitochondrial
proteins was significantly reduced in the hippocampus of BD
patients, but not in those suffering from schizophrenia [44].
Spectroscopy showed that BD may be linked to a disorder of
mitochondrial energy metabolism, such as in CPEO, including a
decrease in pH and high energy phosphates in the frontal and
temporal lobes [81-84]. In BD depressed patients, magnetic
resonance spectroscopy with phosphorus 31(31P-MRS) showed a
significant reduction of phosphocreatine (CrP) in the left frontal
lobe, correlating with the severity of depressive symptoms [85].
The decrease of CrP seems to be a trait-dependent phenomenon
rather than state-dependent, especially in the DB II [86]. Similar
results were seen in patients with mitochondrial encephalo-
myopathy [87, 88].
Accumulating evidence suggests that mithocondrial
dysfunction, especially the impairment of the complex I, is
associated with increased oxidative damage, but it is unclear if this
relationship is specific to BD [81]. Postmortem prefrontal cortex
were assessed using immunoblotting, spectrophotometric and
competitive enzyme immunoassay to identify group differences in
the expression and activity of complex I, and in oxidative damage
in mitocondria. The level of NDUFS7 and complex I activity were
decreased significantly in BD patients, but not in unipolar
depressed or schizophrenic patients. Protein oxidation was
increased only in the BD group; moreover, levels of 3-nitrosyne
were increased in the BD and schizophrenia groups. Therefore, it
can be concluded that an impairment of complex I may be
associated with increased protein oxidation and nitration in the
prefrontal cortex of patients affected by BD. As a result, the
complex I activity and mitochondrial dysfunctions may be potential
therapeutic targets for BD [89].
At peripheral level, leukocyte mitochondrial DNA (mtDNA)
was examined in 35 patients with BD by the nested PCR method.
The PCR product corresponding to the common deletion was found
in 2 of 35 (5.7%) patients, and in 50% of patients with CPEO or
KSS [90]. The deletion involves a region that encodes for five
tRNAs and some subunits of NADH dehydrogenase, cytochrome-c
oxidase and ATP synthase [74]. Although the correlation between
Marazziti et al.
this mutation and the pathophysiology of the BD is unclear,
deletions of mtDNA in the brain could alter energy metabolism and
determine the progression of affective symptoms. Currently, it is
debatable if the deletion observed in BD patients is inherited or not,
or whether this mutation is associated with BD.
As already mentioned, mitochondria play an important roles in
the regulation of intracellular Ca2+ concentration. The diffusion of
Ca2+ from mitochondria to the cytosol has important consequences
for the synthesis and release of neurotransmitters, receptor
signalling, the action potential and synaptic plasticity [91-93] A
dysregulation of Ca2+ in the mitochondria might trigger the
initiation of neural apoptosis [94].
ANXIETY DISORDERS
In spite of the high prevalence of anxiety disorders worldwide,
the data on mithocondrial alterations in these conditions are quite a
few.
Panic attacks and specific phobias have been reported in
patients with the 3243A> G mutation [52,95]. There is a general
increase in the prevalence of anxiety disorders in the first and
second-degree relatives of children with maternally-inherited
mitochondrial diseases, as compared with families of children with
other metabolic disorders of similar severity, but no conclusion can
be drawn from these scattered findings.
AUTISM AND ATTENTION DEFICIT HYPERACTIVITY
DISORDER (ADHD)
Autism and ADHD are developmental disorders: the first is
characterized by impaired social interaction and communication,
and by restricted and repetitive behaviors, while the typical features
of ADHD are the coexistence of attentional deficit with
hyperactivity.
The evidence regarding these two disorders are sporadic,
mostly case reports, but are suggestive. An autistic child showed a
point mutation of the mtDNA in a tRNA gene (G8363A) [96]. In a
boy with a small deletion of mtDNA in mitochondrial tRNA
(deletion of one of three T:A nucleotide pairs in the
tRNALeu(UUR) gene of the mtDNA involving positions 3271 to
3273) and a progressive disorder that led to the death at age 23,
hyperactivity and disciplinary problems were reported
retrospectively during school years [97]. Two subjects with ADHD
were found to be carriers of a mutation of mtDNA [98]. Finally,
symptoms suggestive of ADHD in adolescence, were observed in a
middle-aged woman with rearrangements in mtDNA [72].
In a recent study, mitochondrial dysfunctions and mtDNA
abnormalities were evaluated in lymphocytes from 10 children with
autism and 10 control subjects. The results showed that the NADH
oxydative and the c complex i activities, were significantly lower in
autistic than in healthy children.
Taken together, the results of these studies would suggest that
autistic children are more likely to show mitochondrial
dysfunctions than normal children, although the pathophysiological
role of such alterations is not yet clarified 99].
ALZHEIMER’S DISEASE
Alzheimer’s disease is the most common neurodegenerative
disorder (about two-thirds of all dementias) [100]. It affects both
sexes, with a preference for women, regardless of their longer life
[101-103].
Alzheimer's disease is clinically characterized by a progressive
worsening of cognitive functions. From a macroscopic point of
view the most striking feature is a marked atrophy of the brain
which determines an increased width of the grooves and of cerebral
Mitochondrial Alterations and Neuropsychiatric Disorders
ventricular volume, while the major neuropathological features are
represented by intracellular gles and extracellular amyloid beta
(Abeta) deposits in some brain regions.
Over the past decade, the hypothesis of the involvement of
oxidative stress in the pathogenesis of Alzheimer's disease has been
progressively strengthened by a growing number of publications
[104]. It was, in fact, suggested that mithocondria may play a
crucial role in the mechanisms underlying neurodegeneration. The
major theory of aging suggests that alterations in mitochondrial
genes, such as deletions and point mutations that accumulate
progressively with age as the "common deletion", the most frequent
deletion of 4977 bp found in the mtDNA, can help to reduce the
functionality of one or more respiratory chain complexes, thus
blocking the mechanism of electron transport and increasing the
level of free radical generation with a consequent damage to
mtDNA 2005) [105-112].
The mitochondrial dysfunction is probably one of the earliest
events that are established in the course of Alzheimer's disease: the
appearance of metabolic abnormalities seem to precede the onset of
clinical illness of a decade [113,114]. Interestingly, Abeta
monomers and oligomers are associated with mithocondrial
membranes
A valuable tool to determine whether any mitochondrial
polymorphisms may act as susceptibility or protective factors in the
onset of Alzheimer's disease has been provided by analysis of
mitochondrial haplogroups: mtDNA polymorphisms may make an
individual more susceptible to such a damage and start earlier the
apoptotic mechanism; on the other hand, other polymorphisms may
improve the activity of oxidative phosphorylation and / or reduce
the production of free radicals.
Some markers of mitochondrial alterations have been observed
in post-mortem brains and in blood cells from patients with
Alzheimer's disease, in particular decreased levels of cytochrome
oxidase activity and pyruvate dehydrogenase [115]. In addition,
increased production of free radicals, lipid peroxidation, oxidative
protein damage, coupled with decreased ATP production have been
reported [116]. More recent studies have highlighted also changes
of mitochondria structure in brain specimens [117].
CONCLUSIONS
A growing body of evidence suggests that mitochondrial
dysfunctions may be involved in the pathophysiology of different
neuropsychiatric disorders, given their key role in the cell energy
metabolism. Moreover, they would greatly contribute to the process
of neural apoptosis that should be at the basis of neurodegenerative
disorders, such as schizophrenia, Alzheimer’s dementia and the
most severe forms of BD. In addition, data are available that
mithocondrial abnormalities are present also in developmental
disorders, such as autism and ADHD, and in mood and anxiety
disorders, although the studies aiming at elucidating the role of
mithocondria in the onset and pathophysiology of all these
conditions is just at its dawn.
If the attempts to treat or supplement patients with mood
disorders, schizophrenia and Alzheimer’s disease, with antioxidants
have produced mixed results, currently increasing efforts are
directed towards the development of drugs targeting mithocondria
and/or protecting them from oxidative stress. Such a therapeutic
approach seems to be promising even for the control of a broad
range of conditions, from aging to cancer and diabetes.
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