title: Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis.
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.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.|Qs' Research Institute, Otsuka Pharmaceutical, Tokushima, Japan.
authors.forename: N
authors.identifier: 0000-0002-0124-0634
authors.initials: N
authors.lastname: Yoshimi
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical, Tokushima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Futamura
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S E
authors.initials: SE
authors.lastname: Bergen
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Iwayama
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ishima
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Sellgren
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C J
authors.initials: CJ
authors.lastname: Ekman
authors.affiliation: Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Jakobsson
authors.affiliation: Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Pålsson
authors.affiliation: Tokushima Research Institute, Otsuka Pharmaceutical, Tokushima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kakumoto
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical, Tokushima, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ohgi
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Institute of Neuroscience and Physiology, Section of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Landén
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000328:Adult; D000818:Animals; D001714:Bipolar Disorder / Q000134:cerebrospinal fluid / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000134:cerebrospinal fluid / Q000378:metabolism*; D007523:Isocitrates / Q000378:metabolism; D008297:Male; D055432:Metabolomics / Q000379:methods; D008928:Mitochondria / Q000378:metabolism; D051381:Rats
chemical_list: D007523:Isocitrates; C034219:isocitric acid; D007521:Isocitrate Dehydrogenase