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  • Yoshimi, N. (author)

Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis

  • Article/chapterEnglish2016

Publisher, publication year, extent ...

  • 2016-01-19
  • Springer Science and Business Media LLC,2016

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/248287
  • https://gup.ub.gu.se/publication/248287URI
  • https://doi.org/10.1038/mp.2015.217DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:134635024URI

Supplementary language notes

  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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, postmortem 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.

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Added entries (persons, corporate bodies, meetings, titles ...)

  • Futamura, T. (author)
  • Bergen, S. E.Karolinska Institutet (author)
  • Iwayama, Y. (author)
  • Ishima, T. (author)
  • Sellgren, C.Karolinska Institutet (author)
  • Jakobsson, JoelGothenburg University,Göteborgs universitet,Karolinska Institutet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xjakjo (author)
  • Jakobsson, JoelGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xjakjo (author)
  • Pålsson, Erik,1975Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xpaler (author)
  • Kakumoto, K. (author)
  • Ohgi, Y. (author)
  • Yoshikawa, T. (author)
  • Landén, Mikael,1966Karolinska Institutet,Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry(Swepub:gu)xlandt (author)
  • Hashimoto, K. (author)
  • G, Welches O. R. V. P. (author)
  • Karolinska InstitutetInstitutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi (creator_code:org_t)

Related titles

  • In:Molecular Psychiatry: Springer Science and Business Media LLC21:11, s. 1504-15101359-41841476-5578

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