Mitochondrial DNA (mtDNA) and schizophrenia

The poorly understood aetiology of schizophrenia is known to involve a major genetic contribution even though the genetic factors remain elusive. Most genetic studies are based on Mendelian rules and focus on the nuclear genome, but current studies indicate that other genetic mechanisms are probably involved. This review focuses on mitochondrial DNA (mtDNA), a maternally inherited, 16.6-Kb molecule crucial for energy production that is implicated in numerous human traits and disorders. The aim of this review is to summarise the studies that have explored mtDNA in schizophrenia patients and those which provide evidence for its implication in this illness. Alterations in mitochondrial morphometry, brain energy metabolism, and enzymatic activity in the mitochondrial respiratory chain suggest a mitochondrial dysfunction in schizophrenia that could be related to the genetic characteristics of mtDNA. Moreover, evidence of maternal inheritance and the presence of schizophrenia symptoms in patients suffering from a mitochondrial disorder related to an mtDNA mutation suggest that mtDNA is involved in schizophrenia. The association of specific variants has been reported at the molecular level; however, additional studies are needed to determine whether the mitochondrial genome is involved in schizophrenia.     

Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.     

Mitochondrial DNA HV lineage increases the susceptibility to schizophrenia among Israeli Arabs

Haplotypes and haplogroups are linked sets of common DNA variants, acting as susceptibility or protective factors to complex disorders. Growing evidence suggests that dysfunction of mitochondrial bioenergetics contributes to the schizophrenia phenotype. We studied mitochondrial DNA haplogroups in schizophrenia patients. Since mitochondria are inherited from the mothers, we used healthy fathers as an ideal case-control group. Analysis of the distribution of mitochondrial haplogroups in schizophrenia patients compared to their healthy fathers (202 pairs) resulted in an over-representation of the mtDNA lineage cluster, HV, in the patients (p=0.01), with increased relative risk (odds ratio) of 1.8. Since mitochondrial DNA is small relative to nuclear DNA, a total mitochondrial genome analysis was possible in a hypothesis-free manner. However, mitochondrial DNA haplogroups are highly variable in human population and it will be necessary to replicate our results in other human ethnic groups.     

Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation

Mitochondrial disorders are frequently caused by mutations in mitochondrial genes and usually present as multisystem disease. One of the most frequent mitochondrial mutations is the A3,243G transition in the tRNALeu(UUR) gene. The phenotypic expression of the mutation is variable and comprises syndromic or non-syndromic mitochondrial disorders. Among the syndromic manifestations the mitochondrial encephalopathy, lactacidosis, and stroke-like episode (MELAS) syndrome is the most frequent. In single cases the A3,243G mutation may be associated with maternally inherited diabetes and deafness syndrome, myoclonic epilepsy and ragged-red fibers (MERRF) syndrome, MELAS/MERRF overlap syndrome, maternally inherited Leigh syndrome, chronic external ophthalmoplegia, or Kearns-Sayre syndrome. The wide phenotypic variability of the mutation is explained by the peculiarities of the mitochondrial DNA, such as heteroplasmy and mitotic segregation, resulting in different mutation loads in different tissues and family members. Moreover, there is some evidence that additional mtDNA sequence variations (polymorphisms, haplotypes) influence the phenotype of the A3,243G mutation. This review aims to give an overview on the actual knowledge about the genetic, pathogenetic, and phenotypic implications of the A3,243G mtDNA mutation.     

Mitochondrial diseases

Since the first reports of disorders associated with mitochondrial DNA (mtDNA) defects more than a decade ago, the small mtDNA circle has been a Pandora's box of pathogenic mutations associated with human diseases. The "morbidity map" of mtDNA has gone from one point mutation and a few deletions in 1988 to more than 110 point mutations as of September, 2001. Nuclear DNA defects affecting mitochondrial function and mtDNA replication and integrity have also been identified in the past few years and more are expected. As a result, human "mitochondrial" diseases have evolved beyond the novelty diagnoses of a decade ago into an important area of medicine, and thus, the diagnostic principles of these disorders ought to be familiar to the clinician. In this article, the authors, we summarize the principles of mitochondrial genetics and discuss the common phenotypes, general diagnostic approach, and possible therapeutic venues for these fascinating disorders.     

Mitochondrial dysfunction in bipolar disorder

Mitochondrial dysfunction is implicated in bipolar disorder based on the following lines of evidence: 1) Abnormal brain energy metabolism measured by 31 P‐magnetic resonance spectroscopy, that is, decreased intracellular pH, decreased phosphocreatine (PCr), and enhanced response of PCr to photic stimulation. 2) Possible role of maternal inheritance in the transmission of bipolar disorder. 3) Increased levels of the 4977‐bp deletion in mitochondrial DNA (mtDNA) in autopsied brains. 4) Comorbidity of affective disorders in certain types of mitochondrial disorders, such as autosomal inherited chronic progressive external ophthalmoplegia and mitochondrial diabetes mellitus with the 3243 mutation. Based on these findings, we searched for mtDNA mutations/polymorphisms associated with bipolar disorder and found that 5178C and 10398A polymorphisms in mtDNA were risk factors for bipolar disorder. The 5178C genotype was associated with lower brain intracellular pH. mtDNA variations may play a part in the pathophysiology of bipolar disorder through alteration of intracellular calcium signaling systems. The mitochondrial dysfunction hypothesis, which comprehensively accounts for the pathophysiology of bipolar disorder, is proposed.     

What Can Mitochondrial DNA Analysis Tell Us About Mood Disorders?

Variants in mitochondrial DNA (mtDNA) and nuclear genes encoding mitochondrial proteins in bipolar disorder, depression, or other psychiatric disorders have been studied for decades, since mitochondrial dysfunction was first suggested in the brains of patients with these diseases. Candidate gene association studies initially resulted in findings compatible with the mitochondrial dysfunction hypothesis. Many of those studies, however, were conducted with modest sample sizes (N < 1000), which could cause false positive findings. Furthermore, the DNA samples examined in these studies, including genome-wide association studies, were generally derived from peripheral tissues. One key unanswered question is whether there is an association between mood disorders and somatic mtDNA mutations (deletions and point mutations) in brain regions that accumulate a high amount of mtDNA mutations and/or are involved in the regulation of mood. Two lines of robust evidence supporting the importance of mtDNA mutations in brain tissues for mood disorders have come from clinical observation of mitochondrial disease patients who carry primary mtDNA mutations or accumulate secondary mtDNA mutations due to nuclear mutations and an animal model study. More than half of mitochondrial disease patients have comorbid mood disorders, and mice with neuron-specific accumulation of mtDNA mutations show spontaneous depression-like episodes. In this review, we first summarize the current knowledge of mtDNA and its genetics and discuss what mtDNA analysis tells us about neuropsychiatric disorders based on an example of Parkinson’s disease. We also discuss challenges and future directions beyond mtDNA analysis toward an understanding of the pathophysiology of “idiopathic” mood disorders.     

Systematic association studies of mitochondrial DNA variations in schizophrenia: focus on the ND5 gene

Postmortem studies, as well as genetic association studies, have implicated mitochondrial dysfunction in schizophrenia (SZ). We conducted multistaged analysis to assess the involvement of mitochondrial DNA (mtDNA) variations in SZ. Initially, the entire mtDNA genome was sequenced in pools of DNA from SZ cases and controls (n = 180 in each group, set 1). Two polymorphisms localized to the NADH dehydrogenase subunit 5 (ND5) gene demonstrated suggestive case control allele frequency differences (mtDNA 13368 G/A, p = .019 and mtDNA 13708G/A, p = .043). Hence, the ND5 gene was sequenced in individual samples from the initial panel of cases and controls. Additional subjects from another independent set of cases and controls (set 2, cases, n = 244, controls n = 508) were also sequenced individually. No significant differences in allele frequencies for mtDNA 13368 G/A, and mtDNA 13708G/A were observed. However, we identified 216 other rare variants, 53 of which were reported earlier in association studies of other mitochondrial disorders. We compared the distribution of polymorphisms in both sets of cases and controls. No significant case-control differences were observed in the smaller, first set. In the second set, cases had more variants overall (p = 0.014), as well as synonymous variants (p = 0.02), but the difference for nonsynonymous variants was not significant (p = 0.19). Screening available first-degree relatives (n = 10) revealed 10 maternally inherited variations, suggesting that not all the variants are somatic mutations. Further investigations are warranted.     

Analysis of the fyn kinase gene in Alzheimer's disease and schizophrenia]

Reelin is a protein which plays an important role in cell construction and proliferation of neurons during the development of the central nervous system. Several lines of evidence suggest a possible role for reelin-related genes in the etiology of neurodevelopmental as well as neurodegenerative diseases. It is possible that variations in reelin-related genes (Reelin, VLDLR, FYN, CNRs, a3b1INTEGRIN, mDAB1) may be involved in the pathogenesis of schizophrenia and Alzheimer's disease. We have been conducting a systematic survey of the association of reelin-related gene polymorphisms with these disorders. Previously, we examined the association of the triplet repeats of the reelin and VLDLR gene with schizophrenia. We found no significant association of schizophrenia with the trinucleotide repeat polymorphism of the reelin nor VLDLR genes (Akahane et al. 2002). In this study, we performed an allelic association analysis in Alzheimer's disease and schizophrenia with three polymorphisms of the fyn gene reported by Ishiguro et al (2000). Diagnosis was based on DSM-IV and NINCDS-ADRDA. We found no significant differences in genotype distribution or allelic frequency between patient and control groups. Thus, it is unlikely that these polymorphisms play an important role in the pathogenesis of Alzheimer's disease or schizophrenia.     

An A8296G mutation in the MT-TK gene of a patient with epilepsy - a disease-causing mutation or rare polymorphism?

Mitochondrial DNA (mtDNA) mutations are an important cause of human diseases. mtDNA could be considered a candidate modifying factor in neurodegenerative disorders. A homoplasmic A8296G mutation was detected in a 24-year-old patient with idiopathic generalized epilepsy. The A8296G mutation in the mitochondrial DNA MT-TK gene has been associated with severe mitochondrial diseases. The pathogenicity of this mutation or its association with a specific disease is unclear. This mutation has already been reported exclusively as well as together with other mutations during trials of mtDNA. As in this case, the mutation was homoplasmic and there were no clinical findings in other family members. We suggest that this mutation is a rare polymorphism or may be a pathogenic mutation in combination with other mutations outside of the MT-TK gene.     

Mitochondria, mitochondrial DNA and Alzheimer's disease. What comes first?

To date, the beta amyloid (Abeta) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The mitochondria play central role in the bioenergetics of the cell and apoptotic cell death. In the past 20 years research has been directed at clarifying the involvement of mitochondria and defects in mitochondrial oxidative phosphorylation in late-onset neurodegenerative disorders, including AD. Morphological, biochemical and genetic abnormalities of the mitochondria in several AD tissues have been reported. Impaired mitochondrial respiration, particularly COX deficiency, has been observed in brain, platelets and fibroblasts of AD patients. The "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress and accumulation of Abeta, which in a vicious cycle reinforces the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria in the cascade of events leading to AD, and we will try to provide an answer to the question "what comes first".     

Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis

Several lines of evidence link mutations and deletions in mitochondrial DNA (mtDNA) and its maternal inheritance to neurodegenerative diseases in the elderly. Age-related mutations of mtDNA modulate the tricarboxylic cycle enzyme activity, mitochondrial oxidative phosphorylation capacity and oxidative stress response. To investigate the functional relevance of specific mtDNA polymorphisms of inbred mouse strains in the proteostasis regulation of the brain, we established novel mitochondrial congenic mouse lines of Alzheimer’s disease (AD). We crossed females from inbred strains (FVB/N, AKR/J, NOD/LtJ) with C57BL/6 males for at least ten generations to gain specific mitochondrial conplastic strains with pure C57BL/6 nuclear backgrounds. We show that specific mtDNA polymorphisms originating from the inbred strains differentially influence mitochondrial energy metabolism, ATP production and ATP-driven microglial activity, resulting in alterations of cerebral β-amyloid (Aβ) accumulation. Our findings demonstrate that mtDNA-related increases in ATP levels and subsequently in microglial activity are directly linked to decreased Aβ accumulation in vivo, implicating reduced mitochondrial function in microglia as a causative factor in the development of age-related cerebral proteopathies such as AD.     

Inherited and somatic mitochondrial DNA mutations in Guam amyotrophic lateral sclerosis and parkinsonism-dementia

There is increasing evidence for mitochondrial dysfunction in neurodegenerative disorders, although the exact role of mitochondrial DNA (mtDNA) mutations in this process is unresolved. We investigated inherited and somatic mtDNA substitutions and deletions in Guam amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD). Hypervariable segment 1 sequences of Chamorro mtDNA revealed that the odds ratio of a PD or ALS diagnosis was increased for individuals in the E1 haplogroup while individuals in the E2 haplogroup had decreased odds of an ALS or PD diagnosis. Once the disorders were examined separately, it became evident that PD was responsible for these results. When the entire mitochondrial genome was sequenced for a subset of individuals, the nonsynonymous mutation at nucleotide position 9080, shared by all E2 individuals, resulted in a significantly low odds ratio for a diagnosis of ALS or PD. Private polymorphisms found in transfer and ribosomal RNA regions were found only in ALS and PD patients in the E1 haplogroup. Somatic mtDNA deletions in the entire mtDNA genome were not associated with either ALS or PD. We conclude that mtDNA haplogroup effects may result in mitochondrial dysfunction in Guam PD and reflect Guam population history. Thus it is reasonable to consider Guam ALS and PD as complex disorders with both environmental prerequisites and small genetic effects.     

Mitochondrial Etiology of Neuropsychiatric Disorders

The brain has the highest mitochondrial energy demand of any organ. Therefore, subtle changes in mitochondrial energy production will preferentially affect the brain. Considerable biochemical evidence has accumulated revealing mitochondrial defects associated with neuropsychiatric diseases. Moreover, the mitochondrial genome encompasses over a thousand nuclear DNA genes plus hundreds to thousands of copies of the maternally inherited mitochondrial DNA (mtDNA). Therefore, partial defects in either the nuclear DNA or mtDNA genes or combinations of the two can be sufficient to cause neuropsychiatric disorders. Inherited and acquired mtDNA mutations have recently been associated with autism spectrum disorder, which parallels previous evidence of mtDNA variation in other neurological diseases. Therefore, mitochondrial dysfunction may be central to the etiology of a wide spectrum of neurological diseases. The mitochondria and the nucleus communicate to coordinate energy production and utilization, providing the potential for therapeutics by manipulating nuclear regulation of mitochondrial gene expression.     

Infantile-onset disorders of mitochondrial replication and protein synthesis

Most inherited mitochondrial diseases in infants result from mutations in nuclear genes encoding proteins with specific functions targeted to the mitochondria rather than primary mutations in the mitochondrial DNA (mtDNA) itself. In the past decade, a growing number of syndromes associated with dysfunction resulting from tissue-specific depletion of mtDNA have been reported in infants. MtDNA depletion syndrome is transmitted as an autosomal recessive trait and causes respiratory chain dysfunction with prominent neurological, muscular, and hepatic involvement. Mendelian diseases characterized by defective mitochondrial protein synthesis and combined respiratory chain defects have also been described in infants and are associated with mutations in nuclear genes that encode components of the translational machinery. In the present work, we reviewed current knowledge of clinical phenotypes, their relative frequency, spectrum of mutations, and possible pathogenic mechanisms responsible for infantile disorders of oxidative metabolism involved in correct mtDNA maintenance and protein production.     

Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder

CONTEXT: Variation at the DAOA/G30 locus has been described to be associated with both schizophrenia and bipolar disorder, but there is little consistency between studies of the tested polymorphisms or variants showing association. OBJECTIVES: To obtain a stringent replication of association in large samples of both disorders using consistent clinical and laboratory methods, and to test the hypothesis that association at DAOA/G30 identifies an underlying domain of psychopathological abnormalities that cuts across traditional diagnostic categories. DESIGN: A systematic study of polymorphisms at DAOA/G30 using genetic case-control association analysis. SETTING: Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. PARTICIPANTS: White persons from the United Kingdom meeting criteria for DSM-IV schizophrenia (n = 709) or bipolar I disorder (n = 706) and 1416 ethnically matched controls. METHODS: Nine polymorphisms that tag common genetic variations at DAOA/G30 were genotyped in all of the individuals, and comparisons were made between affected and unaffected individuals. RESULTS: We identified significant association (P = .01-.047) between 3 single-nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence (P = .002-.02) for association with 4 single-nucleotide polymorphisms in the subset of cases (n = 818) in which episodes of major mood disorder had occurred (gene-wide P = .009). We found a similar pattern of association in bipolar cases and in schizophrenia cases in which individuals had experienced major mood disorder. In contrast, we found no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred (all P>.08). CONCLUSIONS: Despite being originally described as a schizophrenia susceptibility locus, our data suggest that variation at the DAOA/G30 locus does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, our results imply that variation at the DAOA/G30 locus influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories.     

Cell response to oxidative stress induced apoptosis in patients with Leber's hereditary optic neuropathy

OBJECTIVES: Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease in which acute or subacute bilateral visual loss occurs preferentially in young men. Over 95% of LHON cases are associated with one of three mitochondrial DNA (mtDNA) point mutations, but only 50% of men and 10% of women who harbour a pathogenetic mtDNA mutation develop optic neuropathy. This incomplete penetrance and preference for men suggests that additional genetic (nuclear or mitochondrial) and/or environmental factors must modulate phenotype expression in LHON. A role for reactive oxygen species (ROS) in mitochondrial diseases, secondary to mtDNA mutations, or as a result of the direct effect of ROS cytotoxicity, has been implicated in many mitochondrial disorders, including LHON. The purpose of this study was to investigate the role of oxidative stress induced apoptosis in LHON. METHODS: The 2-deoxy-D-ribose induced apoptotic response of peripheral blood lymphocytes from six patients with LHON and six healthy subjects was investigated using light microscopy, flow cytometry, agarose gel electrophoresis, and the measurement of mitochondrial membrane potential. RESULTS: Cells of patients with LHON had a higher rate of apoptosis than those of controls and there was evidence of mitochondrial involvement in the activation of the apoptotic cascade. CONCLUSIONS: These differences in oxidative stress induced apoptosis are in line with the hypothesis that redox homeostasis could play a role in the expression of genetic mutations in different individuals and could represent a potential target in the development of new therapeutic strategies.     

Pathogenic mitochondrial DNA mutations in protein-coding genes

More than 200 disease-related mitochondrial DNA (mtDNA) point mutations have been reported in the Mitomap (http://www.mitomap.org) database. These mutations can be divided into two groups: mutations affecting mitochondrial protein synthesis, including mutations in tRNA and rRNA genes; and mutations in protein-encoding genes (mRNAs). This review focuses on mutations in mitochondrial genes that encode proteins. These mutations are involved in a broad spectrum of human diseases, including a variety of multisystem disorders as well as more tissue-specific diseases such as isolated myopathy and Leber hereditary optic neuropathy (LHON). Because the mitochondrial genome contains a large number of apparently neutral polymorphisms that have little pathogenic significance, along with secondary homoplasmic mutations that do not have primary disease-causing effect, the pathogenic role of all newly discovered mutations must be rigorously established. A scoring system has been applied to evaluate the pathogenicity of the mutations in mtDNA protein-encoding genes and to review the predominant clinical features and the molecular characteristics of mutations in each mtDNA-encoded respiratory chain complex.     

Developmental pathology, dopamine, stress and schizophrenia

Psychological stress is a contributing factor for a wide variety of neuropsychiatric diseases including substance use disorders, anxiety, depression and schizophrenia. However, it has not been conclusively determined how stress augments the symptoms of these diseases. Here we review evidence that the ventral hippocampus may be a site of convergence whereby a number of seemingly discrete risk factors, including stress, may interact to precipitate psychosis in schizophrenia. Specifically, aberrant hippocampal activity has been demonstrated to underlie both the elevated dopamine neuron activity and associated behavioral hyperactivity to dopamine agonists in a verified animal model of schizophrenia. In addition, stress, psychostimulant drug use, prenatal infection and select genetic polymorphisms all appear to augment ventral hippocampal function that may therefore exaggerate or precipitate psychotic symptoms. Such information is critical for our understanding into the pathology of psychiatric disease with the ultimate aim being the development of more effective therapeutics.     

Mitochondrial haplogroups and hypervariable region polymorphisms in schizophrenia: A case-control study

Previous studies have detected associations between mitochondrial haplogroups and schizophrenia (SZ). However, no study has examined the relationship between major mitochondrial DNA (mtDNA) haplogroups and SZ in the Chinese population. The aim of this study was to assess the association between mtDNA haplogroups and SZ genesis in the Chinese Han population. We used a case-control study and sequenced the mtDNA hypervariable regions (HVR1, HVR2, and HVR3) in the Han population. We analyzed mtDNA haplogroups and HVR polymorphisms in 298 SZ patients and 298 controls. The haplotypes were classified into 10 major haplogroups: A, B, CZ, D, F, G, M, N, N9a, and R. Statistical analysis revealed that only N9a showed a nominally significant association with protection from SZ [1.68% vs. 6.38%, p=0.004, OR=0.251 (0.092–0.680); after adjustment for age and sex: p=0.006, OR=0.246 (0.090–0.669)]. Three HVR polymorphisms were found to be nominally significantly different between subjects with SZ and controls, and all except one (m.204T>C) are linked to the N9a haplogroup. Our results indicate that mtDNA haplogroup N9a might be a protective factor for SZ.