Mitochondrial Dysfunction In Bipolar Disorder Research Articles

Metabolomics analysis of cerebrospinal fluid suggests citric acid cycle aberrations in bipolar disorder

Mounting evidence indicates mitochondrial dysfunction in bipolar disorder pathophysiology. Here, we employed Proton Nuclear Magnetic Resonance Spectroscopy (1H NMR) of cerebrospinal fluid (CSF) samples from well-characterized bipolar disorder patients (n ​= ​67) and healthy controls (n ​= ​55) in order to measure absolute concentrations of multiple metabolites. Focusing on four citric acid cycle metabolites — citrate, glucose, lactate, and pyruvate — we found higher concentrations of both citrate and glucose in patients compared with controls after correcting for age, sex and body mass index, but only the difference in CSF citrate survived correction for multiple comparisons. Within the patient group, CSF citrate concentrations were higher among lithium users than non-users. In conclusion, this report adds further evidence for a mitochondrial dysfunction in bipolar disorder.

The Role of Mitonuclear Incompatibility in Bipolar Disorder Susceptibility and Resilience Against Environmental Stressors

It has been postulated that mitochondrial dysfunction has a significant role in the underlying pathophysiology of bipolar disorder (BD). Mitochondrial functioning plays an important role in regulating synaptic transmission, brain function, and cognition. Neuronal activity is energy dependent and neurons are particularly sensitive to changes in bioenergetic fluctuations, suggesting that mitochondria regulate fundamental aspects of brain function. Vigorous evidence supports the role of mitochondrial dysfunction in the etiology of BD, including dysregulated oxidative phosphorylation, general decrease of energy, altered brain bioenergetics, co-morbidity with mitochondrial disorders, and association with genetic variants in mitochondrial DNA (mtDNA) or nuclear-encoded mitochondrial genes. Despite these advances, the underlying etiology of mitochondrial dysfunction in BD is unclear. A plausible evolutionary explanation is that mitochondrial-nuclear (mitonuclear) incompatibility leads to a desynchronization of machinery required for efficient electron transport and cellular energy production. Approximately 1,200 genes, encoded from both nuclear and mitochondrial genomes, are essential for mitochondrial function. Studies suggest that mitochondrial and nuclear genomes co-evolve, and the coordinated expression of these interacting gene products are essential for optimal organism function. Incompatibilities between mtDNA and nuclear-encoded mitochondrial genes results in inefficiency in electron flow down the respiratory chain, differential oxidative phosphorylation efficiency, increased release of free radicals, altered intracellular Ca2+ signaling, and reduction of catalytic sites and ATP production. This review explores the role of mitonuclear incompatibility in BD susceptibility and resilience against environmental stressors.

Mitochondrial Dysfunction in Bipolar Disorder: Pathways, Mechanisms and Implications

Mitochondrial Dysfunction in Bipolar Disorder: Pathways, Mechanisms and Implications

Mitochondrial DNA content and oxidation in bipolar disorder and its role across brain regions

The underlying pathology of bipolar disorder remains unknown, though evidence is accumulating to support a role of mitochondrial dysfunction. In this study, we aim to investigate electron transport chain complex I subunit NDUFS7 protein expression; mtDNA content; common deletion; and oxidation in the Broadmann area 24 (BA24), cerebellum, hippocampus, and prefrontal cortex from patients with bipolar disorder, schizophrenia, and non-psychiatric controls. Here, we demonstrate no changes in NDUFS7 in BA24, cerebellum or hippocampus, increases in mtDNA content in hippocampus of patients with bipolar disorder, and decreases in mtDNA oxidation in patients with bipolar disorder and schizophrenia, respectively. Paired analysis between BA24 and cerebellum reveal increases within NDUFS7 levels and mtDNA content in cerebellum of patients with bipolar disorder or schizophrenia. We found a positive correlation between NDUFS7 and mtDNA content (ND4 and ND5) when combining brain regions. Our study supports the involvement of mitochondrial dysfunction in bipolar disorder and schizophrenia.

Mitochondrial DNA Copy Number Raises the Potential of Left Frontopolar Hemodynamic Response as a Diagnostic Marker for Distinguishing Bipolar Disorder From Major Depressive Disorder.

Background: Given a lack of markers, diagnoses of bipolar disorder (BD) and major depressive disorder (MDD) rely on clinical assessment of symptoms. However, the depressive mood states of BD and depressive symptoms of MDD are often difficult to distinguish, which leads to misdiagnoses, which in turn leads to inadequate treatment. Previous studies have shown that the hemodynamic responses of the left frontopolar cortex measured by near-infrared spectroscopy (NIRS) differ between BD and MDD; these hemodynamic responses are associated with altered mitochondrial metabolism; and mitochondrial DNA copy number (mtDNAcn), an index of mitochondrial dysfunction, tends to decrease in BD and increase in MDD patients. In this study, we confirmed that mtDNAcn trends in opposite directions in BD and MDD. We then determined whether mtDNAcn could enhance the utility of NIRS as a diagnostic marker to distinguish between BD and MDD. Methods: We determined mtDNAcn in peripheral blood samples from 58 healthy controls, 79 patients with BD, and 44 patients with MDD. Regional hemodynamic responses during a verbal fluency task (VFT) in 24 BD patients and 44 MDD patients, matched by age and depression severity, were monitored using NIRS. Results: Measurements of mtDNAcn were lower in BD patients and higher in MDD patients than in controls. The left frontopolar region exhibited the most significant differences in mean VFT-related oxy-Hb changes between the BD and MDD groups. Multivariate logistic regression analysis with variables including age, sex, hemodynamic response of the left frontopolar region, and mtDNAcn showed high accuracy for distinguishing BD from MDD (area under the curve = 0.917; 95% confidence interval = 0.849–0.985). For the BD group, we observed a positive correlation between hemodynamic responses in the left frontopolar region and mtDNAcn, while for the MDD group, we observed a negative correlation. Conclusions: Our findings suggest that the association between hemodynamic response and mitochondrial dysfunction in BD or MDD plays an important role in differentiating the pathophysiological mechanisms of BD from those of MDD.

Lactate in bipolar disorder: A systematic review and meta-analysis.

Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo-planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta-analysis, using standardized means and a random-effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta-analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I2 = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools.

A comparative expression analysis of isocitrate dehydrogenase-3 gene and protein levels in postmortem brain tissues from subjects with bipolar disorder

Mitochondrial dysfunction is currently one of the prevailing hypotheses underlying the pathophysiology of bipolar disorder (BD). Multiple lines of evidence from microarray, neuroimaging and postmortem brain studies reported disturbances in brain energy metabolism, increased oxidative stress and altered production of metabolic compounds, which all support the role of mitochondrial dysfunction in BD.1, 2

Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease.

Mitochondrial DNA sequence data reveals association of haplogroup U with psychosis in bipolar disorder

Converging genetic, postmortem gene-expression, cellular, and neuroimaging data implicate mitochondrial dysfunction in bipolar disorder. This study was conducted to investigate whether mitochondrial DNA (mtDNA) haplogroups and single nucleotide variants (SNVs) are associated with sub-phenotypes of bipolar disorder. MtDNA from 224 patients with Bipolar I disorder (BPI) was sequenced, and association of sequence variations with 3 sub-phenotypes (psychosis, rapid cycling, and adolescent illness onset) was evaluated. Gene-level tests were performed to evaluate overall burden of minor alleles for each phenotype. The haplogroup U was associated with a higher risk of psychosis. Secondary analyses of SNVs provided nominal evidence for association of psychosis with variants in the tRNA, ND4 and ND5 genes. The association of psychosis with ND4 (gene that encodes NADH dehydrogenase 4) was further supported by gene-level analysis. Preliminary analysis of mtDNA sequence data suggests a higher risk of psychosis with the U haplogroup and variation in the ND4 gene implicated in electron transport chain energy regulation. Further investigation of the functional consequences of this mtDNA variation is encouraged.

Psychiatric disorders biochemical pathways unraveled by human brain proteomics.

Approximately 25% of the world population is affected by a mental disorder at some point in their life. Yet, only in the mid-twentieth century a biological cause has been proposed for these diseases. Since then, several studies have been conducted toward a better comprehension of those disorders, and although a strong genetic influence was revealed, the role of these genes in disease mechanism is still unclear. This led most recent studies to focus on the molecular basis of mental disorders. One line of investigation that has risen in the post-genomic era is proteomics, due to its power of revealing proteins and biochemical pathways associated with biological systems. Therefore, this review compiled and analyzed data of differentially expressed proteins, which were found in postmortem brain studies of the three most prevalent psychiatric diseases: schizophrenia, bipolar disorder and major depressive disorders. Overviewing both the proteomic methods used in postmortem brain studies, the most consistent metabolic pathways found altered in these diseases. We have unraveled those disorders share about 21% of proteins affected, and though most are related to energy metabolism pathways deregulation, the main differences found are 14-3-3-mediated signaling in schizophrenia, mitochondrial dysfunction in bipolar disorder and oxidative phosphorylation in depression.

Lithium‐induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue

Extensive preclinical and clinical evidence suggests mitochondrial dysfunction in bipolar disorder. Studies of brain energy metabolism in bipolar disorder suggest an impairment of energy generation by mitochondrial oxidative phosphorylation. Lithium is an effective drug widely used in treating bipolar disorder, but its mechanism of action has remained uncertain. The aim of this study was to clarify the effect of lithium on mitochondrial oxidative phosphorylation. We spectrophotometrically determined the activities of the respiratory chain complexes I + III [antimycin A-sensitive nicotinamide adenine dinucleotide (NADH) cytochrome c oxidorductase], complexes II + III (succinate cytochrome c oxidoreductase), succinate dehydrogenase, and complex IV [cytochrome c oxidase (COX)], and of the mitochondrial matrix enzyme citrate synthase in postmortem human brain cortex homogenates following exposure to lithium (up to 10 mM). Activities of complexes I + III and of complexes II + III were dose-dependently increased by lithium with maximum values at 1 mM (165%, p = 0.03, and 146%, p = 0.00002, of controls). Activity of succinate dehydrogenase remained unchanged up to 2 mM, but was raised at higher drug concentrations (maximum 220%, p = 0.01, of controls). In contrast, activity of COX was not significantly affected by the drug (decrease of 12% at 1 mM, p = 0.4). Our study suggests that lithium stimulates mitochondrial respiratory chain enzyme activities at clinically relevant concentrations. Lithium's effect on the mitochondrial respiratory chain presents further evidence of the pathophysiological significance of mitochondrial dysfunction in bipolar disorder. The effect may be relevant to the therapeutic efficacy of the drug by potentially reversing a disease-related alteration.

Mitochondrial DNA haplogroup analysis in patients with bipolar disorder

Several lines of evidence support mitochondrial dysfunction in bipolar disorder. Elevated calcium level in platelets is reported in this disease. To verify mitochondrial DNA (mtDNA) haplogroups characteristic to bipolar disorder, we sequenced mtDNA of seven regions and performed haplogroup analysis in 195 patients with bipolar disorder and 255 controls. They belonged to 16 major mtDNA haplogroups, A, B4, B5, C, D4, D5, F, G, M7, M8, M9, M10-12, N9a, N9b, Y, and Z. The logistic regression analysis revealed that the haplogroup N9a was over-represented in bipolar disorder. We also performed a case-control study for two functional mtDNA polymorphisms, mtDNA5460G > A and 12358A > G, that altered intracellular calcium dynamics. While the mtDNA5460G > A polymorphism was not associated with bipolar disorder, the mtDNA12358A > G polymorphism was associated with bipolar disorder in 199 patients with bipolar disorder and 260 controls. However, this association was not replicated in an independent sample set. Possible significances of these findings are discussed.

Abnormal cellular energy and phospholipid metabolism in the left dorsolateral prefrontal cortex of medication‐free individuals with bipolar disorder: an in vivo1H MRS study

While the pathophysiology of bipolar disorder (BD) remains to be elucidated, postmortem and neuroimaging studies have suggested that abnormalities in the dorsolateral prefrontal cortex (DLPFC) are implicated. We compared the levels of specific brain chemicals of interest measured with proton magnetic resonance spectroscopy ((1)H MRS) in medication-free BD subjects and age- and gender-matched healthy controls. We hypothesized that BD subjects would present abnormal cellular metabolism within the DLPFC, as reflected by lower N-acetyl-aspartate (NAA) and creatine + phosphocreatine (Cr + PCr). Thirty-two medication-free BD subjects (33.8 +/- 10.2 years) and 32 matched controls (33.8 +/- 9.0 years) underwent a short echo-time (TE = 30 ms) (1)H MRS. An 8-cm(3) single voxel was placed in the left DLPFC, and individual concentrations of NAA, Cr + PCr, choline-containing compounds (GPC + PC), myo-inositol, and glutamate were obtained, using the water signal as an internal reference. BD subjects had lower Cr + PCr [F((1,62)) = 5.85; p = 0.018; one-way analysis of variance (ANOVA)] and lower GPC + PC [F((1,62)) = 5.79; p = 0.019; one-way ANOVA] levels in the left DLPFC. No significant differences were observed for other brain metabolites. These findings provide further evidence that the pathophysiology of BD involves impairment in the DLPFC. Our findings can be interpreted as evidence for reduced cellular energy and phospholipid metabolism, consistent with the hypothesis of mitochondrial dysfunction in BD.

Mitochondrial Dysfunction as the Molecular Basis of Bipolar Disorder

Multiple lines of evidence, such as impaired energy metabolism in the brain detected by magnetic resonance spectroscopy, a possible role of maternal inheritance, co-morbidity with mitochondrial diseases, the effects of mood stabilisers on mitochondria, increased mitochondrial DNA (mtDNA) deletion in the brain, and association with mtDNA mutations/polymorphisms or nuclear-encoded mitochondrial genes, suggest that mitochondrial dysfunction is an important component of bipolar disorder. Global reduction of mitochondria-related gene expression in the postmortem brains of patients with bipolar disorder may also be an indicator, but such findings are affected by sample pH and thus need to be interpreted with caution. A recently developed animal model carrying mtDNA deletion in neurons suggested that accumulation of mtDNA deletions causes bipolar disorder-like phenotypes. The next step in the study of mitochondrial dysfunction in bipolar disorder should be clarification of how mitochondrial dysfunction, a nonspecific risk factor, can cause specific symptoms of bipolar disorder. Two hypothetical mechanisms are mtDNA neuroplasticity and nonvisual photoreception impairment. Further study of mitochondrial dysfunction in bipolar disorder is expected to be useful for the development of new mood stabilisers.

The Role of Mitochondrial Dysfunction in Bipolar Disorder

Altered energy metabolism and accumulated mitochondrial DNA (mtDNA) mutations in the brain, associated mtDNA polymorphisms/mutations or nuclear encoded mitochondrial genes, effects of mood stabilizers on mitochondria and comorbidity of mood disorders with mitochondrial disorders, together suggest the role of mitochondrial dysfunction in the pathophysiology of bipolar disorder. Mitochondrial dysfunction may be involved in the calcium signaling abnormality found in bipolar disorder. We recently produced mice accumulating neuron-specific mtDNA deletions. Bipolar disorder-like behavioral phenotypes of these mice supported this hypothesis. Thus, development of new mood stabilizers acting on mitochondrial function might be warranted.

Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research

Magnetic resonance spectroscopy (MRS) affords a noninvasive window on in vivo brain chemistry and, as such, provides a unique opportunity to gain insight into the biochemical pathology of bipolar disorder. Studies utilizing proton ((1)H) MRS have identified changes in cerebral concentrations of N-acetyl aspartate, glutamate/glutamine, choline-containing compounds, myo-inositol, and lactate in bipolar subjects compared to normal controls, while studies using phosphorus ((31)P) MRS have examined additional alterations in levels of phosphocreatine, phosphomonoesters, and intracellular pH. We hypothesize that the majority of MRS findings in bipolar subjects can be fit into a more cohesive bioenergetic and neurochemical model of bipolar illness that is both novel and yet in concordance with findings from complementary methodological approaches. In this review, we propose a hypothesis of mitochondrial dysfunction in bipolar disorder that involves impaired oxidative phosphorylation, a resultant shift toward glycolytic energy production, a decrease in total energy production and/or substrate availability, and altered phospholipid metabolism.

Mitochondrial DNA 3243A>G mutation and increased expression of LARS2 gene in the brains of patients with bipolar disorder and schizophrenia

Accumulating evidence suggests mitochondrial dysfunction in bipolar disorder. Analyses of mitochondria-related genes using DNA microarray showed significantly increased LARS2 (mitochondrial leucyl-tRNA synthetase) in the postmortem prefrontal cortices of patients with bipolar disorder provided by the Stanley Foundation Brain Collection. LARS2 is a nuclear gene encoding the enzyme catalyzing the aminoacylation of mitochondrial tRNA(Leu). A well-studied mitochondrial DNA point mutation, 3243A>G, in the region of tRNA(Leu (UUR)), related with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), is known to decrease the efficiency of aminoacylation of tRNA(Leu (UUR)). The steady state level of LARS2 was examined in the transmitochondrial cybrids carrying 3243A>G. We examined the 3243A>G mutation in these brains using the peptide nucleic acid-clamped polymerase chain reaction restriction fragment length polymorphism method. LARS2 was upregulated in the transmitochrondrial cybrids carrying 3243A>G. The 3243A>G was detected in the postmortem brains of two patients with bipolar disorder and one with schizophrenia. These patients also showed higher levels of the mutation in their livers and significantly higher gene expression of LARS2 compared with other subjects. These results suggest that upregulation of LARS2 is a hallmark of 324A>G mutation. The accumulation of 3243A>G mutation in the brain may have a pathophysiologic role in bipolar disorder and schizophrenia.

Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis

Accumulating evidence suggests that mitochondrial dysfunction underlies the pathophysiology of bipolar disorder (BD) and schizophrenia (SZ). We performed large-scale DNA microarray analysis of postmortem brains of patients with BD or SZ, and examined expression patterns of mitochondria-related genes. We found a global down-regulation of mitochondrial genes, such as those encoding respiratory chain components, in BD and SZ samples, even after the effect of sample pH was controlled. However, this was likely due to the effects of medication. Medication-free patients with BD showed tendency of up-regulation of subset of mitochondrial genes. Our findings support the mitochondrial dysfunction hypothesis of BD and SZ pathologies. However, it may be the expression changes of a small fraction of mitochondrial genes rather than the global down-regulation of mitochondrial genes. Our findings warrant further study of the molecular mechanisms underlying mitochondrial dysfunction in BD and SZ.

Molecular evidence for mitochondrial dysfunction in bipolar disorder.

The disease mechanism of bipolar disorder remains unknown. Recent studies have provided evidence for abnormal gene expression in bipolar disorder. To determine the expression of 12558 nuclear genes in the human hippocampus in healthy control subjects and those with bipolar disorder or schizophrenia. We used gene arrays to study messenger RNA expression. Data were verified with a real-time quantitative polymerase chain reaction assay. We studied 10 healthy control subjects, 9 subjects with bipolar disorder, and 8 subjects with schizophrenia. The expression of nuclear messenger RNA coding for mitochondrial proteins was significantly decreased in the hippocampus in subjects with bipolar disorder but not in those with schizophrenia. Subjects with bipolar disorder were characterized by a pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation and the adenosine triphosphate-dependent process of proteasome degradation. These findings point toward a widespread dysregulation of mitochondrial energy metabolism and downstream deficits of adenosine triphosphate-dependent processes in bipolar disorder.