You are on page 1of 8

DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 16: 136 143 (2010)

THE ROLE

OF IN

MITOCHONDRIAL DYSFUNCTION PSYCHIATRIC DISEASE


Fernando Scaglia*

Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Childrens Hospital, Houston, Texas

Mitochondrial respiratory chain disorders are a group of genetically and clinically heterogeneous disorders caused by the biochemical complexity of mitochondrial respiration and the fact that two genomes, one mitochondrial and one nuclear, encode the components of the respiratory chain. These disorders can manifest at birth or present later in life. They result, at least in part, in defective production of ATP. Typically, mitochondrial disorders affect tissues with high energetic demands such as skeletal muscle, cardiac muscle, and the central nervous system. Neurological dysfunction is the most frequent clinical presentation of these disorders. The central nervous system is highly dependent on oxidative metabolism, and particular mitochondrial disorders are accompanied by focal brain necrosis (Leigh disease), dementia, or static encephalopathy. Furthermore, many children with mitochondrial encephalomyopathies present with more subtle and indolent signs including focal cognitive deficits of memory, perception, and language. Some subjects with mitochondrial disorders may also exhibit nonverbal cognitive impairment, compromised visuospatial abilities, and short-term memory deficits associated with working memory that likely reflect defects in synaptic plasticity. Psychiatric features are found within the clinical spectrum of mitochondrial syndromes. It is increasingly recognized that mitochondrial dysfunction may be associated with neuropsychiatric abnormalities such as dementia, major depression, and bipolar disorder. Furthermore, several lines of evidence suggest that there is involvement of mitochondrial dysfunction in schizophrenia, including documented alterations in brain energy metabolism, electron transport chain activity, and expression of genes involved in mitochondrial function. The purpose of this review article is to summarize the psychiatric features observed in mitochondrial cytopathies and discuss possible mechanisms of dysfunctional cellular energy metabolism that underlie the pathophysiology of major subsets of ' 2010 Wiley-Liss, Inc. psychiatric disorders.
Dev Disabil Res Rev 2010;16:136143.

Key Words: mitochondrial dysfunction; psychiatric disease; bipolar disorder; schizophrenia; major depressive disorder

PSYCHIATRIC SYMPTOMS IN MITOCHONDRIAL CYTOPATHIES tudies have shown a potential association of primary mitochondrial disease with comorbid psychiatric problems, including major depressive disorder, psychosis, bipolar disorder, anxiety disorders, and personality change. Indeed, symptoms of mental illness have been previously documented in subjects affected with mitochondrial cytopathies. Fattal et al. [2006] summarized several case reports of subjects having different mitochondrial diseases who exhibited features evocative of mental disorders. Depression was reported in a proband with autosomal dominant progressive external ophthalmoplegia (PEO) and

multiple mitochondrial DNA (mtDNA) deletions in several tissues [Suomalainen et al., 1992]. The onset of depression was noted several years before the onset of CPEO. In the probands autopsy, a greater percentage of mDNA deletions was observed in the brain than in skeletal muscle. Several family members of this proband exhibited depression [Suomalainen et al., 1992]. In these subjects, depression may be regarded as an expression of mitochondrial encephalomyopathy. Bipolar affective disorder has been observed in autosomal dominant PEO caused by mutations in the ANT1 gene [Siciliano et al., 2003]. More recently, mutations in two other nuclear genes that regulate mitochondrial function, C10ORF2 and POLG1, have also been implicated in mood disorders [Spelbrink et al., 2001; Van Goethem et al., 2001; Van Goethem et al., 2003; Luoma et al., 2004; Mancuso et al., 2004]. Mental disorders have been documented as a frequent comorbidity of the m.3243 A>G transition in the mitochondrial tRNALeu(UUR) (MTTL1) gene that is commonly associated with the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome [Kaufmann et al., 2009]. Patients with MELAS syndrome have a high prevalence of auditory or visual hallucinations, depression, delusions of persecution, and erratic behaviors. The increased prevalence of neurobehavioral features seems not to be limited to patients with MELAS, but almost one third of their asymptomatic carrier relatives have depression (4). Some patients carrying the m.3243 A>G mutation in the MTTL1 gene have reportedly developed schizophrenia [Prayson and Wang, 1998; Ueda et al., 2004] and other psychotic disorders [Yamazaki et al., 1991; Suzuki et al., 1997; Thomeer et al., 1998]. A case of MELAS syndrome where mania preceded diagnosis has been reported [Grover et al., 2006]. In addition, a patient with the clinical diagnosis of MELAS syndrome diagnosed with acute neurological deficits suggestive of a cerebrovascular accident had rapid remission of symptoms and no evidence of focal lesions; he also had a psychiatric episode with

*Correspondence to: Fernando Scaglia, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Childrens Hospital, Clinical Care Center, Suite 1560, 6621 Fannin, Mail Code CC1560, Houston, TX 77030. E-mail: fscaglia@bcm.tmc.edu Received 5 July 2010; Accepted 17 July 2010 View this article online at wileyonlinelibrary.com. DOI: 10.1002/ddrr.115

' 2010 Wiley -Liss, Inc.

unusual visual hallucinations and anxiety disorder [Kiejna et al., 2002]. The course of dementia in MELAS syndrome tends to progress independently of the remitting and relapsing cycle of the stroke-like episodes, as characterized by both cognitive and emotional disorders leading to personality changes and gradual loss of ability to function in daily life [Pachalska et al., 2001]. Patients with mitochondrial diabetes mellitus caused by low heteroplasmic load of the same mutation frequently exhibit depression as comorbidity [Miyaoka et al., 1997; Onishi et al., 1997]. Another mutation (3274 G>A transition) in the MTTL1 gene has been associated with a neuropsychiatric syndrome and cataracts [Jaksch et al., 2001]. Furthermore, an m.3256 C>T mutation in the same gene has been associated with psychosis and progressive dementia [Amemiya et al., 2000]. In summary, these findings suggest a potential role of mtDNA mutations, and in particular the m.3243 A>G mtDNA mutation, in the etiology and pathomechanism of psychiatric disorders. Nevertheless, none of the 300 patients with schizophrenia [Odawara et al., 1998] who were screened were found to harbor the m.3243 A>G mutation in peripheral blood cells as detected by PCR-RFLP. Thus, the previously reported cases might represent coincidental comorbidity of the two disorders due to the high incidence of mental illness in the general population. However, it cannot be completely ruled out that the m.3243 A>G mutation is related to mental disorders. EVIDENCE FOR MITOCHONDRIAL DYSFUNCTION IN PSYCHIATRIC ILLNESS A Schizophrenia Mode of inheritance Prior evidence has suggested increased maternal transmission of schizophrenia [Shimizu, Kurachi et al., 1987; Goldstein et al., 1990; Wolyniec et al., 1992], which evokes a possible role of maternally inherited mtDNA. However, most cases of schizophrenia in the general population are sporadic [Yang et al., 2009]. This finding would implicate the accumulation of somatic mtDNA mutations rather than the presence of germline mtDNA mutations as a possible underlying mechanism of mitochondrial dysfunction in mental illness.
Dev Disabil Res Rev


Ultrastructure studies of mitochondrial abnormalities Electron microscopic studies have demonstrated mitochondrial abnormalities in subjects with psychiatric disorders, particularly schizophrenia. A striking decrease in mitochondrial number and density in oligodendrocytes has been observed in the prefrontal cortex and caudate nucleus in the postmortem brains of subjects with schizophrenia [Uranova et al., 2001]. In addition, decreases in the number of mitochondria have been found in the axonal terminal in caudate and putamen sections in untreated subjects with schizophrenia when compared to treated subjects and control subjects suggesting that neuroleptic treatment may normalize the number of mitochondria [Kung and Roberts, 1999]. This observation was further corroborated by another study in which the number of mitochondria was reduced in subjects with schizophrenia not taking antipsychotic medications in comparison with control subjects [Inuwa et al., 2005]. In addition, monocyte and lymphocyte mitochondria of schizophrenic patients appeared swollen when compared to controls [Inuwa et al., 2005]. Altered metabolic activity and neuroimaging studies Brain energy metabolism has been evaluated in subjects with psychiatric disorders by using 31phosphorus magnetic resonance spectroscopy (31PMRS) to measure cerebral membrane phospholipids and high-energy phosphates. A decrease in phosphodiester values and an increased ratio of phosphomonoesters/phosphodiesters was observed in the frontal cortex of subjects with schizophrenia compared to control subjects [Volz et al., 1997]. Decreased levels of ATP in the basal ganglia and temporal lobes of subjects with schizophrenia were also observed with 31P-MRS [Kegeles et al., 1998]. However, expression of creatine kinase, an enzyme involved in the synthesis and metabolism of phosphocreatine, was not decreased when compared to control subjects [MacDonald et al., 2006]. Positron emission tomography (PET) scans with [18F]-fluoro-deoxy-glucose (FDG) have demonstrated metabolic decreases in schizophrenia. Decreased right lentiform nucleus and temporal lobe metabolic rates have also been detected in subjects with schizophrenia compared to control subjects [Buchsbaum and Hazlett, 1998].


Altered mitochondrial gene expression and biochemical studies Several studies have reported generalized mitochondrial dysfunction in psychiatric disorders using microarray technology to survey nuclear gene expression [Middleton et al., 2002; Sokolov et al., 2003; Konradi et al., 2004; Prabakaran et al., 2004; Altar et al., 2005; Iwamoto et al., 2005]. The expression of a set of genes involved in oxidative phosphorylation was not decreased in subjects with schizophrenia in the hippocampus by microarray studies nor in the prefrontal cortex by PCR analysis [Konradi et al., 2004]. Yet, an expression microarray and proteomics study performed in a set of dorsolateral prefrontal cortex samples from the Stanley Array Collection found mitochondrial dysfunction in schizophrenia [Prabakaran et al., 2004]. The Stanley Medical Research Institute assembled the Array Collection for high-throughput array technologies. It contains brain samples from 35 individuals in each of three diagnostic groups: schizophrenia, bipolar disorder, and unaffected control subjects. The specimens were collected, processed, and stored in a standardized way, following informed consent, by participating medical examiners between January 1995 and June 2002. Decreased mitochondrial gene expression was found in hippocampal dentate granule neurons sampled with laser capture microscopy by microarray study [Altar et al., 2005]. However, hippocampal gene expression profiles related to mitochondrial energy metabolism may be very dependent upon pH [Mexal et al., 2006]. These studies suggest that pH differences in postmortem brain samples may affect the expression of nuclear-encoded genes related to mitochondrial function, and therefore, the interpretation of postmortem brain studies involving mitochondrial gene expression must be carefully monitored against the strong effect of agonal-pH state. pH functions as a surrogate marker for lactic acid accumulation in the brain that is triggered by hypoxia. Several studies have suggested that alterations in the activity of complex IV, and in particular expression of the COII (cytochrome c oxidase subunit II), could underlie the pathological mechanism of schizophrenia. Complex IV activity was found to be unchanged [Mulcrone et al., 1995] or decreased [Cavelier et al., 1995] in frontal lobes. mRNA expression of complex IV subunits was increased in the frontal lobes [Whatley et al., 1998], putamen [Prince et al., 1999], and nucleus accumbens [Prince et al., 1999] 137

Mitochondrial Dysfunction in Psychiatric Disease

Scaglia

but decreased in the caudate [Prince et al., 1999]. Furthermore, studies in brains of rats chronically treated with classical neuroleptics have revealed decreased COII expression with increased complex IV activity [Prince et al., 1997]. Another study investigated expression in the postmortem brain of the 13 mitochondrial DNA-encoded subunits of the respiratory chain in a cohort of subjects with schizophrenia, major depressive disorder, and bipolar disorder compared to matched control subjects [Shao et al., 2008]. The chosen specimens were from subjects who all had rapid deaths, as prolonged death was previously shown to increase mtDNA copy number. Expression results suggested decreased mitochondrial transcription occurred in subjects with schizophrenia. However, when mtDNA transcripts were normalized to expression of the mtDNA D-loop control region, no expression differences were seen. Common and novel mitochondrial DNA SNPs The published literature has implicated that mitochondrial genome sequence variations may be associated with schizophrenia. The entire mtDNA genome of subjects with schizophrenia has been evaluated only in peripheral tissues, such as blood. In one study, the entire mitochondrial genomes from six unrelated subjects with schizophrenia that resulted from apparent maternal transmission and from their schizophrenic mothers were sequenced [Martorell et al., 2006]. The six subjects with schizophrenia had 50 mtDNA variants compared to the revised Cambridge reference sequence. The variants were not preferentially located in a specific area of the mitochondrial genome. The heteroplasmic variant in the MTND4 gene, m.12096 T>A, was found in five of the six mother/offspring schizophrenic pairs. In this study, one subject carried two other variants previously associated with bipolar disorder in complex I (the MT-ND5 variant m.12403 C>T and the MT-ND5 variant m.12950 A>C). Another approach has been to evaluate the frequency of specific polymorphisms in subjects with schizophrenia. The ratio of the heteroplasmic MT-ND4 variant 12027C to the reference 12027T sequence was evaluated in the leukocytes of subjects with schizophrenia relative to control subjects [Marchbanks et al., 2003]. There was a significant increase in the variant rich fraction in leukocytes from subjects with schizophrenia. The whole mitochondrial genome was sequenced 138

in two subjects with schizophrenia who had decreased complex IV activity in postmortem brain and in two subjects with the same condition who had a pedigree suggesting maternal inheritance [Lindholm et al., 1997]. Five substitutions in coding regions were found that had not previously been described as polymorphisms. These five substitutions were then studied in 81 schizophrenic patients and five control groups. Two polymorphisms in the MT-CYB gene, m.14793A>G and m15218A>G (causing non-synonymous amino acid substitutions), were more frequently observed in schizophrenia. However, the results did not lend strong support to the association of a particular mtDNA substitution conveying an increased risk for schizophrenia. Overall, performing whole mtDNA genome sequencing in peripheral blood in subjects with psychiatric disorders may not provide a clear answer as it is possible that some heteroplasmic mtDNA mutations or variants, even if present in brain tissue of these subjects, could be selected out from peripheral blood and other rapidly dividing tissues. More recently, based on the occurrence of psychiatric features in MELAS, the common m.3243 A>G mutation was examined in the prefrontal cortex and liver in subjects with major depressive disorder, bipolar disorder, schizophrenia, and control subjects. Of 57 subjects with roughly equal numbers of subjects per group, one subject with schizophrenia was identified to harbor this heteroplasmic mutation in prefrontal cortex and liver, while no subjects with major depressive disorder or control subjects were identified to carry this mutation [Munakata et al., 2005]. However, the m.3243 A>G mutation in this study was not detected by conventional PCR-RFLP. Rather, the low levels of heteroplasmy were identified by peptide nucleic acid (PNA)-clamped PCR-RFLP. The observed m.3243 A>G mutation in the brain in this subject with schizophrenia could represent a somatic event associated with the generation of reactive oxygen species. It is also plausible that a small percentage of the m.3243 A>G mutation may be found in control brain specimens. Single mitochondrial DNA deletions and mitochondrial DNA copy number variants The large 4,977 base-pair common deletion is the most frequent deletion in mtDNA [Wallace et al., 1987]. It was initially reported that there was an increased frequency of this common deletion in the cerebral cortex of


subjects with bipolar disorder when compared to age-matched control subjects [Kato et al., 1997]. However, only few subjects participated in that study and those findings could not be confirmed by a second study performed in a larger number of subjects with schizophrenia and bipolar disorder as well as control subjects [Sabunciyan et al., 2007]. When common deletion levels were assayed in another study by comparing subjects with schizophrenia and control subjects, no changes were observed, despite observing reduced levels of cytochrome c oxidase enzymatic activity in the frontal cortex and caudate nucleus of subjects with schizophrenia. Thus, cytochrome c oxidase activity did not correlate with levels of the mtDNA 4,977 base-pair deletion [Cavelier et al., 1995]. Another research group failed to see an increase in the common deletion in subjects with schizophrenia or even an age-related increase in the common deletion [Kakiuchi et al., 2005]. More recently, the amount of mtDNA common deletion was screened in brain tissues of subjects with schizophrenia. No significantly increased frequency of the mtDNA common deletion was found in schizophrenia [Shao et al., 2008]. The lack of consistency in detecting the mtDNA common deletion in these studies may relate to the different age groups of these subjects, as one would expect to see age-related increases in deletion load. Moreover, the technology used may also influence the detection rate. B Mood Disorders Mode of inheritance It has been observed that patients with manic depressive illness more frequently have affected mothers than fathers, as well as a predominance of affected maternal relatives [Winokur and Reich, 1970]. It has been suggested that bipolar disorder may be caused by maternal inheritance [McMahon et al., 1995]. However, a more recent study suggested multifactorial inheritance in maternally inherited pedigrees and a single major gene in paternally inherited pedigrees [Grigoroiu-Serbanescu et al., 1998]. Ultrastructural studies Ultrastrucural studies have not been reported in brains of subjects with major depressive disorder or bipolar disorder. Altered metabolic activity and neuroimaging studies Decreases in intracellular pH and phosphocreatine and altered phospho

Dev Disabil Res Rev

Mitochondrial Dysfunction in Psychiatric Disease

Scaglia

creatine response to photic stimulation in the frontal lobes have been noted in patients with bipolar disorder [Deicken et al., 1995; Hamakawa et al., 1999]. To further support the hypothesis of altered brain energy metabolism in mental illness, the expression of creatine kinase seems to be downregulated in the dorsolateral prefrontal cortex in subjects with bipolar disorder [MacDonald et al., 2006]. PET scans with (18F)-fluoro-deoxy-glucose (FDG) have shown metabolic decreases in bipolar disorder and in major depressive disorder [alMousawi et al., 1996]. In major depressive disorder, reduced metabolic rates have been determined in prefrontal cortex, anterior cingulated cortex, and caudate nucleus [Videbech, 2000]. Furthermore, depressed subjects with bipolar disorder exhibit reduced whole-brain metabolism compared to manic subjects with bipolar disorder [Strakowski et al., 2000]. When the results of proton (1H)-MRS and 31P-MRS studies in bipolar subjects compared to healthy control subjects were reviewed [Stork and Renshaw, 2005], the authors hypothesized that the basis of mitochondrial dysfunction in bipolar disorder may involve impaired oxidative phosphorylation, a shift toward glycolytic energy production, decreased total energy production and/or substrate availability, and altered phospholipid metabolism. Overall, these data suggest that dysfunction of energy metabolism is found in the brains of subjects affected with bipolar disorder and major depressive disorder. Elucidating the basis of this dysfunction may provide novel insight into the pathomechanism underlying psychiatric illnesses. Altered mitochondrial gene expression The expression of mitochondrial genes was downregulated in the dorsolateral prefrontal cortex of subjects with bipolar disorder compared to controls when using brain samples from the Stanley array collection [Iwamoto et al., 2005]. Conversely, the same authors found increased expression of mitochondrial genes in a subgroup of untreated subjects with bipolar disorder [Iwamoto et al., 2005]. The authors initially suggested that prior exposure to antipsychotic medications might have exerted a modulatory effect on gene expression. However, this subgroup had an increased brain pH when compared to controls, and pH may have also exerted an effect on gene expression. The expression of a set of genes involved in oxidative phosphorylation
Dev Disabil Res Rev


was decreased in the hippocampus by expression array studies and in the prefrontal cortex by PCR in subjects with bipolar disorder [Konradi et al., 2004]. However, in another study, after correcting for pH, there was no evidence of nuclear-encoded mitochondrial dysregulation in the anterior cingulated cortex, dorsolateral prefrontal cortex, and cerebellum for either bipolar disorder or major depressive disorder [Vawter et al., 2006]. As previously mentioned in the section focused on schizophrenia, hippocampal gene expression in samples from subjects with mood disorders seems to depend upon pH, especially for gene expression profiles related to mitochondrial energy metabolism [Mexal et al., 2006]. pH differences in postmortem brain samples may affect the expression of nuclear-encoded genes related to mitochondrial function. However, as lowered intracellular pH has been shown by brain 31P-MRS to occur in bipolar disorder that may indicate that mitochondrial dysfunction may predate conditions surrounding death to produce different physiological responses that are relevant to cellular bioenergetics [Hamakawa et al., 2004]. However, results suggestive that there is reduced in vivo pH in bipolar disorder have not been reproduced. Using RNA microarray technology to analyze gene expression profiles in postmortem frontal cortex of subjects with bipolar disorder, another research group [Sun et al., 2006] found several genes differentially expressed in subjects with bipolar disorder compared to controls, including genes controlling the electron transport chain (ETC), phosphatidylinositol-signaling system, glycolysis, and gluconeogenesis. Messenger RNA levels of identified genes (NDUFS7, UQCRC2, COX6C, and ATP5G3 representing complexes I, III, IV, and V) were quantified using realtime PCR, with results showing downregulation of NADH-ubiquinone oxidoreductase 20-kDa subunit (ETC complex I), cytochrome c oxidase polypeptide Vic (ETC complex IV), and ATP synthase lipid-binding protein (ETC complex V). Significantly increased expression of the LARS2 gene was found by analyses of mitochondria-related genes using DNA microarray in the postmortem prefrontal cortices of patients with bipolar disorder provided by the Stanley Foundation Brain Collection. This gene encodes a mitochondrial leucyl-tRNA synthetase that catalyzes the aminoacylation of the mitochondrial tRNALeu(UUR) [Sohm


et al., 2003; Sohm et al. 2004]. The m.3243 A>G mutation associated with MELAS syndrome was detected in the postmortem brains of two patients with bipolar disorder. The LARS2 gene was upregulated in transmitochondrial cybrids carrying the m.3243 A>G transition, reflecting the accumulation of this mutation [Munakata et al., 2005]. It has been speculated that the upregulation of the LARS2 gene in the 3243 cybrids may be due to the copy number difference of mtDNA [Munakata et al., 2005]. Analysis of the expression of the 13 encoded subunits of the respiratory chain and D-loop in brain specimens from subjects with mood disorders revealed that lithium treatment in bipolar disorder was associated with a decrease in expression of all 13 transcripts by 1937% compared to nonlithium treated subjects with bipolar disorder. However, the decrease was not significant for individual mtDNA transcripts investigated in a cohort of subjects with schizophrenia, major depressive disorder, and bipolar disorder compared to matched control subjects [Shao et al. 2008]. After normalizing data using the D-loop as reference, two significantly increased mtDNA-encoded genes were found in brains from subjects with bipolar disorder (MT-ND1 and MT-ND5). When samples from subjects with major depressive disorder were analyzed, the expression results suggested decreased mitochondrial transcription. However, when mtDNA transcripts were normalized to expression of the mtDNA D-loop, no expression differences were observed [Shao et al., 2008]. Unlike schizophrenia, no postmortem biochemical studies have been reported for bipolar disorder. Common and novel mitochondrial DNA SNPs A possible relationship between mtDNA mutations/polymorphisms and bipolar disorder has been investigated ever since mitochondrial dysfunction was first proposed to underlie bipolar disorder [Kato and Kato, 2000]. In some studies, the entire mitochondrial genome of subjects with psychiatric disorders has been evaluated. The entire mtDNA sequence was examined in six subjects with bipolar disorder and comorbid somatic symptoms suggestive of mitochondrial disorders [Munakata et al., 2004]. Several uncharacterized, homoplasmic, nonsynonymous nucleotide substitutions of mtDNA were found. Among them, an m.3644 T>C 139

Mitochondrial Dysfunction in Psychiatric Disease

Scaglia

variant in the MT-ND1 gene was found in 5 of 199 patients but in none of 258 controls. Using transmitochondrial cybrids, this variant was shown to decrease mitochondrial membrane potential and complex I activity compared to haplogroup-matched controls, suggesting that the variant could increase the risk for bipolar disorder [Munakata et al., 2004]. In another study, the entire mtDNA genome from leukocytes in one proband with major depressive disorder and epilepsy from a family with suspected maternal inheritance of bipolar disorder, major depressive disorder, suicide, and other psychotic disorders was sequenced [Munakata et al., 2007]. Comparison of the sequence from the proband to the human reference mtDNA sequence identified 34 base substitutions. All were registered polymorphisms in the mitochondrial database MITOMAP, except for two SNPs: a nonsynonymous SNP in the MTND1 gene (m.3394T>C) and a nonsynonymous SNP in the MT-ATP6 (m.9115A>G). In another study, the mtDNA from leukocytes of seven subjects with atypical psychosis was sequenced [Kazuno et al., 2005]. In this study, 67 SNPs were found in comparison to the revised Cambridge reference sequence. Because two subjects belonged to the subgroup F1ba within haplogroup N, this led the investigators to hypothesize that this particular mitochondrial haplogroup may be a predisposing factor for atypical psychosis. Nevertheless, these results could not be reproduced in another study where the mitochondrial genome from 25 subjects with bipolar disorder and family history suggestive of maternal inheritance and control subjects was sequenced [Kirk et al., 1999]. Kato et al. [2000; 2001] searched for mtDNA polymorphisms associated with bipolar disorders by heteroduplex analysis and SSCP. The authors reported that the m.10398 G>A (MT-ND3) and the m.5178 A>C (MT-ND1) were both significantly associated with bipolar disorder. Mc Mahon et al. [2000] sequenced the entire mitochondrial genome in nine unrelated probands selected from large pedigrees with exclusive maternal transmission of bipolar disorder. Fifteen variants of possible pathological significance were screened in subjects and controls classified into major groups comprising the European mtDNA haplogroups. There were no significant differences in haplogroup frequencies between patients with bipolar disorder and control subjects. Although four variants (including the 140

m.10398 G>A) had odds ratios higher than 2 or lower than 0.5, the authors concluded that there was no association between mtDNA variants and bipolar disorder. The common m.3243 A>G mutation was examined in the prefrontal cortex and liver in a group that was comprised of subjects with mental illnesses including major depressive disorder and bipolar disorder, and in control subjects, as previously mentioned in the section focusing on schizophrenia. Two

I subunit gene) promoter were associated with bipolar disorder in Japanese postmortem brain samples and in National Institute of Mental Health samples [Washizuka et al., 2004]. Single mtDNA deletions and mtDNA copy number variants No mtDNA deletions were found by Southern blot analysis of postmortem brain specimens in seven patients with bipolar disorder and nine who committed suicide [Stine et al., 1993]. This group found a marginal increase for the large 4,977 base-pair common deletion in the cerebral cortex of subjects with bipolar disorder when compared to age-matched controls. However, the percentage of heteroplasmy was as low as 0.6%, which would not be expected to cause any significant impairment [Kato et al., 1997]. Few subjects participated in that study and those findings could not be confirmed in a larger cohort of subjects with mental illness including bipolar disorder and control subjects [Sabunciyan et al., 2007]. The results of another study did not reveal an increased frequency of the common deletion in subjects with bipolar disorder or even an age-related increase in the common deletion [Kakiuchi et al., 2005]. Conversely, another study in brain specimens of subjects with bipolar disorder detected an increased frequency of the mtDNA common deletion in bipolar disorder but not in major depressive disorder [Shao et al., 2008]. MtDNA copy number has been evaluated in psychiatric disorders. An association between longer intervals of hypoxia and increased mtDNA copy number in the dorsolateral prefrontal cortex was reported; however, after controlling for effects of hypoxia and agonal duration, there was a trend toward decreased mtDNA copy number in bipolar disorder compared to control subjects [Vawter et al., 2006]. Another group found that the decrease of mtDNA copy number in the postmortem brains of bipolar disorder patients was age dependent. Furthermore, the expression of the POLG1 gene was significantly upregulated in bipolar disorder, suggesting that abnormalities in the mtDNA replication system may underlie the pathological mechanism of bipolar disorder and possibly other psychoses [Kakiuchi et al., 2005]. Animal studies and cellular models Several studies revealed that mood stabilizers such as lithium and other pharmacological compounds used to


Taken together, the picture that emerges from the reviewed lines of evidence, including ultrastructural, neuroradiological, biochemical, and genetic data, as well as the known comorbidity of neuropsychiatric features in mitochondrial disorders, seems to point toward a possible role of mitochondrial dysfunction in the pathological mechanism of bipolar disorder, major depressive disorder, and schizophrenia.
subjects with bipolar disorder were identified with this heteroplasmic mutation in prefrontal cortex and liver, whereas no subjects with major depressive disorder or control subjects carried this mutation [Munakata et al., 2005]. Again, low levels of m.3243 A>G heteroplasmy could reflect a somatic mutation associated with the generation of reactive oxygen species and/or could potentially be found in the brain of control subjects. Nuclear gene polymorphisms Functional polymorphisms of the NDUFV2 (a nuclear-encoded complex


Dev Disabil Res Rev

Mitochondrial Dysfunction in Psychiatric Disease

Scaglia

treat bipolar disorder increase the expression of the anti-apoptotic gene Bcl-2 [Zarate et al., 2006]. Microarray studies in animals suggested that lithium and valproic acid increased energy metabolism and decreased oxidative damage, suggesting that this effect may mediate their mechanism of action in bipolar disorder [Wang et al., 2004]. Similar effects were also found under conditions associated with excitoxicity and oxidative stress [Cui et al., 2007]. Bcl-2 heterozygous mice demonstrated an increase in anxiety-associated behaviors [Einat et al., 2005]. The study suggested that the Bcl-2 gene may play a role in modulating anxiety. Transgenic mice with mtDNA deletions related to mutations in the nuclear-encoded POLG1 gene also displayed abnormal behaviors including decreased cue and contextual fear conditioning, increased startle response, and decreased and distorted day-night rhythm of wheel-running activity compared to normal mice [Kasahara et al., 2006]. POTENTIAL MECHANISMS OF ACTION OF MITOCHONDRIAL DYSFUNCTION IN PSYCHIATRIC DISEASES Taken together, the picture that emerges from the reviewed lines of evidence, including ultrastructural, neuroradiological, biochemical, and genetic data, as well as the known comorbidity of neuropsychiatric features in mitochondrial disorders, seems to point toward a possible role of mitochondrial dysfunction in the pathological mechanism of bipolar disorder, major depressive disorder, and schizophrenia. However, the exact mechanisms by which deficits of energy metabolism occur in the brain of subjects affected with psychiatric disorders are not completely known. Deleterious effects of mitochondrial dysregulation have been implicated in schizophrenia. Oxidative phosphorylation deficiency leads to changes in mitochondrial ATP production, which correlates with reduced ATP levels in the frontal and left temporal lobes of schizophrenic patients [Fujimoto et al., 1992; Volz et al., 2000]. ATP depletion and the ensuing deficiency of the energy dependent Na/K-ATPases and Ca2-ATPases leads to increased Na and Ca2 flux, which impairs plasma membrane potential. An increase of intracellular Ca2 may also lead to defective neurotransmission involving dopamine, glutamate, and GABA
Dev Disabil Res Rev


[Carlsson et al., 1999], dysregulation of apoptosis [Jarskog et al., 2000], and oxidative damage via generation of reactive oxygen species [Mahadik and Scheffer, 1996]. All of these mechanisms could eventually lead to structural remodeling and long-term changes in synaptic plasticity [Smythies, 1999]. Dysfunction of dopamine metabolism, storage, release, or uptake mechanisms in the mesolimbic systems seems to occur in schizophrenia [Laruelle et al., 1999], and a wide range of data suggests that dopamine can inhibit the mitochondrial respiratory system and, in particular, complex I [Brenner-Lavie et al., 2008]. As to the possible involvement of mitochondrial dysfunction in mood dis-

Future studies of mitochondrial dysfunction in subjects affected with psychiatric disorders should shed light on the specific mechanisms by which mitochondrial dysfunction can cause specific symptoms of psychiatric disorders.

orders, this possibility could be linked to a previously developed hypothesis of intracellular signaling alterations [Belmaker, 2004]. Indeed, in mood disorders, there are various abnormalities of second messenger systems including cyclic AMP signaling [Perez et al., 2000], protein kinase C (PKC] signaling [Hahn and Friedman, 1999], and the phosphatidylinositol pathway [Soares and Mallinger, 1997]. Agonist-stimulated calcium response is an important factor in intracellular second-messenger systems and is enhanced in patients with bipolar disorder [Yamawaki et al., 1998]. Because mitochondria play an important role in intracellular sequestration of calcium [Simpson and Russell, 1998], it is possible that mitochondrial dysfunction in subjects with bipolar disorder may directly relate to previously hypothesized dysregulation of the intracellular calcium response and intracellular signaling systems [Kato and Kato, 2000].


SUMMARY Although findings by independent laboratories using different methodologic approaches do provide some evidence to suggest that dysfunction of the mitochondrial ETC may play a role in the pathophysiology of mental illness, several caveats need to be considered. Taken together, expression studies indicate that mitochondrial dysfunction may not be a significant factor in the pathophysiology of mood disorders, as agonal-pH background in postmortem brain tissue affects the expression of nuclear encoded mitochondrial genes and mtDNA copy number. Indeed, after dissecting the effect of the agonal-pH state on gene expression, most differential expression effects are reduced [Vawter et al., 2006]. Other factors such as alcohol dependency and drug abuse may also play a role in observed alterations of mitochondrial-related genes [Sokolov et al., 2003], as these are frequent comorbidities found in individuals with mental illness that confound data analysis. Moreover, some of the studies have been performed in postmortem brain samples of treated subjects. Lithium, the most common pharmacotherapy for bipolar disorder, may improve mitochondrial function [Silverstone et al., 2003]. Conversely, the use of sodium valproate to treat bipolar disorder is known to impair cellular energy metabolism [Bolanos and Medina, 1997]. Thus, confounding conditions and treatment effects need be carefully considered when evaluating potential associations between mitochondrial dysfunction and mood disorders. Searching for single nucleotide polymorphisms (SNPs) in mtDNA that could potentially be associated with schizophrenia, bipolar disorder, or major depressive disorder has led to inconsistent results. Such lack of unanimity could result from either small sample size in some studies or a complex association of various mitochondrial and nuclear genomic variants that, only when present in combination, would lead to mitochondrial dysfunction and psychiatric disorders. Thus far, the majority of studies have failed to implicate any specific gene variant in association with psychiatric disorders. One possible explanation for this finding could be the heterogeneity of clinical phenotypes potentially caused by different genetic variants, as has been observed in schizophrenia [Fanous and Kendler, 2005]. Many studies have largely used mitochondrial genome 141

Mitochondrial Dysfunction in Psychiatric Disease

Scaglia

resequencing of leukocyte DNA, whereas the gold standard methodology is Sanger sequencing to sensitively detect mtDNA variants. However, findings in leukocyte DNA do not invalidate the hypothesis that accumulating mtDNA heteroplasmic mutations in select tissues, such as brain, may be associated with psychiatric disorders. Moreover, it remains possible that mitochondrial dysfunction leading to psychiatric disease may be caused by a specific mtDNA haplogroup in conjunction with nuclear gene variations. Developing animal models having profiles similar to that seen in bipolar disorder and schizophrenia may help to circumvent such contentious issues. Future studies of mitochondrial dysfunction in subjects affected with psychiatric disorders should shed light on the specific mechanisms by which mitochondrial dysfunction can cause specific symptoms of psychiatric disorders. Such work may lead to the development of cellular disease markers and therapies that have the potential to ameliorate aspects of psychiatric disease that are minimally addressed by current therapeutic strategies. n REFERENCES
Al-Mousawi AH, Evans N, et al. 1996. Limbic dysfunction in schizophrenia and mania. A study using 18F-labelled fluorodeoxyglucose and positron emission tomography. Br J Psychiatry 169:509516. Altar CA, Jurata LW, et al. 2005. Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry 58:8596. Amemiya S, Hamamoto M, et al. 2000. Psychosis and progressing dementia: presenting features of a mitochondriopathy. Neurology 55:600601. Belmaker RH. 2004. Bipolar disorder. N Engl J Med 351:476486. Bolanos JP, Medina JM. 1997. Effect of valproate on the metabolism of the central nervous system. Life Sci 60:19331942. Brenner-Lavie H, Klein E, et al. 2008. Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex. I. Relevance to dopamine pathology in schizophrenia. Biochim Biophys Acta 1777:173185. Buchsbaum MS, Hazlett EA. 1998. Positron emission tomography studies of abnormal glucose metabolism in schizophrenia. Schizophr Bull 24:343364. Carlsson A, Waters N, et al. 1999. Neurotransmitter interactions in schizophreniatherapeutic implications. Biol Psychiatry 46:13881395. Cavelier L, Jazin EE, et al. 1995. Decreased cytochrome-c oxidase activity and lack of agerelated accumulation of mitochondrial DNA deletions in the brains of schizophrenics. Genomics 29:217224. Cui J, Shao L, et al. 2007. Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate. Neuroscience 144:14471453.

Deicken RF, Weiner MW, et al. 1995. Decreased temporal lobe phosphomonoesters in bipolar disorder. J Affect Disord 33:195199. Einat H, Yuan P, et al. 2005. Increased anxietylike behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders. Behav Brain Res 165:172180. Fanous AH, Kendler KS. 2005. Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework. Mol Psychiatry 10:613. Fattal O, Budur K, et al. 2006. Review of the literature on major mental disorders in adult patients with mitochondrial diseases. Psychosomatics 47:17. Fujimoto T, Nakano T, et al. 1992. Study of chronic schizophrenics using 31P magnetic resonance chemical shift imaging. Acta Psychiatr Scand 86:455462. Goldstein JM, Faraone SV, et al. 1990. Sex differences in the familial transmission of schizophrenia. Br J Psychiatry 156:819826. Grigoroiu-Serbanescu M, Martinez M, et al. 1998. Patterns of parental transmission and familial aggregation models in bipolar affective disorder. Am J Med Genet 81:397404. Grover S, Padhy SK, et al. 2006. Mania as a first presentation in mitochondrial myopathy. Psychiatry Clin Neurosci 60:774775. Hahn CG, Friedman E. 1999. Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord 1:8186. Hamakawa H, Kato T, et al. 1999. Quantitative proton magnetic resonance spectroscopy of the bilateral frontal lobes in patients with bipolar disorder. Psychol Med 29:639644. Hamakawa H, Murashita J, et al. 2004. Reduced intracellular pH in the basal ganglia and whole brain measured by 31P-MRS in bipolar disorder. Psychiatry Clin Neurosci 58:8288. Inuwa IM, Peet M, et al. 2005. QSAR modeling and transmission electron microscopy stereology of altered mitochondrial ultrastructure of white blood cells in patients diagnosed as schizophrenic and treated with antipsychotic drugs. Biotech Histochem 80: 133137. Iwamoto K, Bundo M, et al. 2005. Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet 14:241253. Jaksch M, Lochmuller H, et al. 2001. A mutation in mt tRNALeu(UUR) causing a neuropsychiatric syndrome with depression and cataract. Neurology 57:19301931. Jarskog LF, Gilmore JH, et al. 2000. Cortical bcl-2 protein expression and apoptotic regulation in schizophrenia. Biol Psychiatry 48:641650. Kakiuchi C, Ishiwata M, et al. 2005. Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia. Int J Neuropsychopharmacol 8:515522. Kasahara T, Kubota M, et al. 2006. Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. Mol Psychiatry 11:577593, 523. Kato T, Kato N. 2000. Mitochondrial dysfunction in bipolar disorder. Bipolar Disord 2:18090. Kato T, Kunugi H, et al. 2000. Association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA. Am J Med Genet 96:182186.


Kato T, Kunugi H, et al. 2001. Mitochondrial DNA polymorphisms in bipolar disorder. J Affect Disord 62:151164. Kato T, Stine OC, et al. 1997. Increased levels of a mitochondrial DNA deletion in the brain of patients with bipolar disorder. Biol Psychiatry 42:871875. Kaufmann P, Engelstad K, et al. 2009. Protean phenotypic features of the A3243G mitochondrial DNA mutation. Arch Neurol 66: 8591. Kazuno AA, Munakata K, et al. 2005. Mitochondrial DNA sequence analysis of patients with atypical psychosis. Psychiatry Clin Neurosci 59:497503. Kegeles LS, Humaran TJ, et al. 1998. In vivo neurochemistry of the brain in schizophrenia as revealed by magnetic resonance spectroscopy. Biol Psychiatry 44:382398. Kiejna A, DiMauro S, et al. 2002. Psychiatric symptoms in a patient with the clinical features of MELAS. Med Sci Monit 8: CS66CS72. Kirk R, Furlong RA, et al. 1999. Mitochondrial genetic analyses suggest selection against maternal lineages in bipolar affective disorder. Am J Hum Genet 65:508518. Konradi C, Eaton M, et al. 2004. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 61:300308. Kung L, Roberts RC. 1999. Mitochondrial pathology in human schizophrenic striatum: a postmortem ultrastructural study. Synapse 31:6775. Laruelle M, Abi-Dargham A, et al. 1999. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 46:5672. Lindholm E, Cavelier L, et al. 1997. Mitochondrial sequence variants in patients with schizophrenia. Eur J Hum Genet 5:406412. Luoma P, Melberg A, et al. 2004. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364: 875882. MacDonald ML, Naydenov A, et al. 2006. Decrease in creatine kinase messenger RNA expression in the hippocampus and dorsolateral prefrontal cortex in bipolar disorder. Bipolar Disord 8:255264. Mahadik SP, Scheffer RE. 1996. Oxidative injury and potential use of antioxidants in schizophrenia. Prostaglandins Leukot Essent Fatty Acids 55:4554. Mancuso M, Filosto M, et al. 2004. POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness. Neurology 62:316318. Marchbanks RM, Ryan M, et al. 2003. A mitochondrial DNA sequence variant associated with schizophrenia and oxidative stress. Schizophr Res 65:3338. Martorell L, Segues T, et al. 2006. New variants in the mitochondrial genomes of schizophrenic patients. Eur J Hum Genet 14: 520528. McMahon FJ, Chen YS, et al. 2000. Mitochondrial DNA sequence diversity in bipolar affective disorder. Am J Psychiatry 157: 10581064. McMahon FJ, Stine OC, et al. 1995. Patterns of maternal transmission in bipolar affective disorder. Am J Hum Genet 56:12771286. Mexal S, Berger R, et al. 2006. Brain pH has a significant impact on human postmortem hippocampal gene expression profiles. Brain Res 1106:111.


142

Dev Disabil Res Rev

Mitochondrial Dysfunction in Psychiatric Disease

Scaglia

Middleton FA, Mirnics K, et al. 2002. Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci 22:27182729. Miyaoka H, Suzuki Y, et al. 1997. Mental disorders in diabetic patients with mitochondrial transfer RNA(Leu) (UUR) mutation at position 3243. Biol Psychiatry 42:524526. Mulcrone J, Whatley SA, et al. 1995. A study of altered gene expression in frontal cortex from schizophrenic patients using differential screening. Schizophr Res 14:203213. Munakata K, Fujii K, et al. 2007. Sequence and functional analyses of mtDNA in a maternally inherited family with bipolar disorder and depression. Mutat Res 617:119124. Munakata K, Iwamoto K, et al. 2005. Mitochondrial DNA 3243A>G mutation and increased expression of LARS2 gene in the brains of patients with bipolar disorder and schizophrenia. Biol Psychiatry 57:525532. Munakata K, Tanaka M, et al. 2004. Mitochondrial DNA 3644T>C mutation associated with bipolar disorder. Genomics 84: 10411050. Odawara M, Arinami T, et al. 1998. Absence of association between a mitochondrial DNA mutation at nucleotide position 3243 and schizophrenia in Japanese. Hum Genet 102: 708709. Onishi H, Kawanishi C, et al. 1997. Depressive disorder due to mitochondrial transfer RNALeu(UUR) mutation. Biol Psychiatry 41:11371139. Pachalska M, DiMauro S, et al. 2001. Pathomechanism and clinical presentation of neurobehavioral disturbances in a patient with MELAS syndrome. Neurol Neurochir Pol 35:681693. Perez J, Tardito D, et al. 2000. Abnormalities of cAMP signaling in affective disorders: implication for pathophysiology and treatment. Bipolar Disord 2:2736. Prabakaran S, Swatton JE, et al. 2004. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9:643,684697. Prayson RA, Wang N. 1998. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: an autopsy report. Arch Pathol Lab Med 122: 978981. Prince JA, Blennow K, et al. 1999. Mitochondrial function is differentially altered in the basal ganglia of chronic schizophrenics. Neuropsychopharmacology 21:372379. Prince JA, Yassin MS, et al. 1997. Neurolepticinduced mitochondrial enzyme alterations in the rat brain. J Pharmacol Exp Ther 280: 261267. Sabunciyan S, Kirches E, et al. 2007. Quantification of total mitochondrial DNA and mitochondrial common deletion in the frontal cortex of patients with schizophrenia and bipolar disorder. J Neural Transm 114:665674. Shao L, Martin MV, et al. 2008. Mitochondrial involvement in psychiatric disorders. Ann Med 40:281295. Shimizu A, Kurachi M, et al. 1987. Morbidity risk of schizophrenia to parents and siblings of schizophrenic patients. Jpn J Psychiatry Neurol 41:6570.

Siciliano G, Tessa A, et al. 2003. Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene. Neuromuscul Disord 13: 162165. Silverstone PH, Wu RH, et al. 2003. Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients. Int Clin Psychopharmacol 18:7379. Simpson PB, Russell JT. 1998. Role of mitochondrial Ca2 regulation in neuronal and glial cell signalling. Brain Res Brain Res Rev 26: 7281. Smythies J. 1999. Redox mechanisms at the glutamate synapse and their significance: a review. Eur J Pharmacol 370:17. Soares JC, Mallinger AG. 1997. Intracellular phosphatidylinositol pathway abnormalities in bipolar disorder patients. Psychopharmacol Bull 33:685691. Sohm B, Frugier M, et al. 2003. Towards understanding human mitochondrial leucine aminoacylation identity. J Mol Biol 328:9951010. Sohm B, Sissler M, et al. 2004. Recognition of human mitochondrial tRNALeu(UUR) by its cognate leucyl-tRNA synthetase. J Mol Biol 339:1729. Sokolov BP, Jiang L, et al. 2003. Transcription profiling reveals mitochondrial, ubiquitin and signaling systems abnormalities in postmortem brains from subjects with a history of alcohol abuse or dependence. J Neurosci Res 72:756767. Spelbrink JN, Li FY, et al. 2001. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 28:223231. Stine OC, Luu SU, et al. 1993. The possible association between affective disorder and partially deleted mitochondrial DNA. Biol Psychiatry 33:141142. Stork C, Renshaw PF. 2005. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry 10:900919. Strakowski SM, DelBello MP, et al. 2000. Neuroimaging in bipolar disorder. Bipolar Disord 2:148164. Sun X, Wang JF, et al. 2006. Downregulation in components of the mitochondrial electron transport chain in the postmortem frontal cortex of subjects with bipolar disorder. J Psychiatry Neurosci 31:189196. Suomalainen A, Majander A, et al. 1992. Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia. J Clin Invest 90:6166. Suzuki Y, Taniyama M, et al. 1997. Diabetes mellitus associated with 3243 mitochondrial tRNA(Leu(UUR)) mutation: clinical features and coenzyme Q10 treatment. Mol Aspects Med 18 Suppl:S181S188. Thomeer EC, Verhoeven WM, et al. 1998. Psychiatric symptoms in MELAS; a case report. J Neurol Neurosurg Psychiatry 64:692693. Ueda Y, Ando A, et al. 2004. A boy with mitochondrial disease: asymptomatic proteinuria without neuromyopathy. Pediatr Nephrol 19:107110.

Uranova N, Orlovskaya D, et al. 2001. Electron microscopy of oligodendroglia in severe mental illness. Brain Res Bull 55: 597610. Van Goethem G, Dermaut B, et al. 2001. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28:211212. Van Goethem G, Lofgren A, et al. 2003. Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. Hum Mutat 22:175176. Vawter MP, Tomita H, et al. 2006. Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders. Mol Psychiatry 11:615, 663679. Videbech P. 2000. PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand 101:1120. Volz HR, Riehemann S, et al. 2000. Reduced phosphodiesters and high-energy phosphates in the frontal lobe of schizophrenic patients: a (31)P chemical shift spectroscopic-imaging study. Biol Psychiatry 47:954961. Volz HP, Rzanny R, et al. 1997. 31P magnetic resonance spectroscopy in the dorsolateral prefrontal cortex of schizophrenics with a volume selective techniquepreliminary findings. Biol Psychiatry 41:644648. Wallace DC, Ye JH, et al. 1987. Sequence analysis of cDNAs for the human and bovine ATP synthase beta subunit: mitochondrial DNA genes sustain seventeen times more mutations. Curr Genet 12:8190. Wang JF, Shao L, et al. 2004. Glutathione S-transferase is a novel target for mood stabilizing drugs in primary cultured neurons. J Neurochem 88:14771484. Washizuka S, Iwamoto K, et al. 2004. Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder in Japanese and the National Institute of Mental Health pedigrees. Biol Psychiatry 56:483489. Whatley SA, Curti D, et al. 1998. Superoxide, neuroleptics and the ubiquinone and cytochrome b5 reductases in brain and lymphocytes from normals and schizophrenic patients. Mol Psychiatry 3:227237. Winokur G, Reich T. 1970. Two genetic factors in manic-depressive disease. Compr Psychiatry 11:9399. Wolyniec PS, Pulver AE, et al. 1992. Schizophrenia: gender and familial risk. J Psychiatr Res 26:1727. Yamawaki S, Kagaya A, et al. 1998. Intracellular calcium signaling systems in the pathophysiology of affective disorders. Life Sci 62:16651670. Yamazaki M, Igarashi H, et al. 1991. A case of mitochondrial encephalomyopathy with schizophrenic psychosis, dementia and neuroleptic malignant syndrome. Rinsho Shinkeigaku 31:12191223. Yang J, Visscher PM, et al. 2009. Sporadic cases are the norm for complex disease. Eur J Hum Genet. DOI: 10.1038/ejhg.2009.177. Zarate CA Jr, Singh J, et al. 2006. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 59:10061020.

Dev Disabil Res Rev

Mitochondrial Dysfunction in Psychiatric Disease

Scaglia

143

You might also like