Abstract
Although evidence for mitochondrial dysfunction in the pathogenesis of bipolar disorder (BD) has been reported, the precise biological basis remains unknown, hampering the search for novel biomarkers. In this study, we performed metabolomics of cerebrospinal fluid (CSF) from male BD patients (n=54) and age-matched male healthy controls (n=40). Subsequently, post-mortem brain analyses, genetic analyses, metabolomics of CSF samples from rats treated with lithium or valproic acid were also performed. After multivariate logistic regression, isocitric acid (isocitrate) levels were significantly higher in the CSF from BD patients than healthy controls. Furthermore, gene expression of two subtypes (IDH3A and IDH3B) of isocitrate dehydrogenase (IDH) in the dorsolateral prefrontal cortex from BD patients was significantly lower than that of controls, although the expression of other genes including, aconitase (ACO1, ACO2), IDH1, IDH2 and IDH3G, were not altered. Moreover, protein expression of IDH3A in the cerebellum from BD patients was higher than that of controls. Genetic analyses showed that IDH genes (IDH1, IDH2, IDH3A, IDH3B) and ACO genes (ACO1, ACO2) were not associated with BD. Chronic (4 weeks) treatment with lithium or valproic acid in rats did not alter CSF levels of isocitrate, and mRNA levels of Idh3a, Idh3b, Aco1 and Aco2 genes in the rat brain. These findings suggest that abnormality in the metabolism of isocitrate by IDH3A in the mitochondria plays a key role in the pathogenesis of BD, supporting the mitochondrial dysfunction hypothesis of BD. Therefore, IDH3 in the citric acid cycle could potentially be a novel therapeutic target for BD.
Highlights
Bipolar disorder (BD) is a major psychiatric disease characterized by episodes of depression and mania or hypomania interspaced by periods of euthymia
There were no differences between healthy controls and BD patients for age and body mass index (Table 1)
We examined whether protein expression of IDH3A and IDH3B in the cerebellum and parietal cortex (BA7) differed between samples from patients with BD, major depressive disorder or schizophrenia, and controls (Supplementary Table S4)
Summary
Bipolar disorder (BD) is a major psychiatric disease characterized by episodes of depression and mania or hypomania interspaced by periods of euthymia. A number of studies of families and twins show the importance of genetic factors affecting susceptibility to BD, the precise pathogenesis of BD is not well understood.[7] BD may be a neuroinflammatory disorder[8] in which relapses are toxic, indicating the importance of early detection to prevent an otherwise negative prognosis.[9] Accumulating evidence suggests that mitochondrial dysfunction plays a key role in the pathogenesis of BD.[10,11,12,13,14,15] A number of findings (for example, calcium dysregulation, disturbed energy metabolism, oxidative phosphorylation abnormalities and abnormalities in cellular resilience and synaptic plasticity) from microarray studies, biochemical studies, neuroimaging studies and post-mortem brain studies all support the role of mitochondrial dysfunction in the pathogenesis of BD.[10,11,12,13,14,15]
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