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

Molecular Psychiatry volume 23, pages 792–793 (2018)Cite this article

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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

We read with great interest, a recent paper by Yoshimi et al.,3 published in Molecular Psychiatry, which performed a thorough metabolomic analysis and found isocitrate to be one of the metabolic compounds significantly elevated in cerebral spinal fluid from patients with BD.3 Isocitrate is produced in the citric acid cycle that gets subsequently converted into alpha-ketoglutarate by isocitrate dehydrogenase (IDH) through oxidative decarboxylation. While there exist three distinct IDH isoforms in humans—IDH1, IDH2 and IDH3—IDH3 (alpha, beta and gamma) is the only isoform that uses NAD+ as a cofactor to concomitantly produce NADH. Activation of this enzyme from the citric acid cycle increases NADH production that fuels oxidative phosphorylation and energy production through the mitochondrial electron transport chain. Subsequent analysis by Yoshimi et al.3 using postmortem brain samples from the Stanley Medical Research Institute (SMRI) revealed decreased expression of IDH3A and IDH3B gene transcripts in dorsolateral prefrontal cortex (DLPFC; Brodmann’s area (BA)46) from subjects with BD. While Dr Yoshimi did not examine IDH3A/B protein levels in the same brain region where gene expression analysis was conducted, he reported reduced protein levels of IDH3A in the cerebellum from subjects with BD and other major psychiatric disorders, including schizophrenia (SCZ) and major depressive disorder (MDD). The study provided further evidence of mitochondrial dysfunction in BD by showing alterations in the metabolism of isocitrate by IDH3 mRNA in the DLPFC, but the question of whether this results in lower levels of IDH3 proteins remains unanswered.

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References

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Acknowledgements

We thank Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number R24MH068855, and Canadian Institutes of Health Research (CIHR) and Camh Foundation as sources of funding in support of this report. GS was supported by the Camh Foundation. LTY and ACA were supported by grants from CIHR.

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  1. Departments of Pharmacology & Toxicology and Psychiatry, University of Toronto, Toronto, ON, Canada

    G Scola, A C Andreazza & L T Young

  2. Centre for Addiction and Mental Health, Toronto, ON, Canada

    G Scola, A C Andreazza & L T Young

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  1. G Scola
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  2. A C Andreazza
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  3. L T Young
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Correspondence to G Scola.

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Scola, G., Andreazza, A. & Young, L. A comparative expression analysis of isocitrate dehydrogenase-3 gene and protein levels in postmortem brain tissues from subjects with bipolar disorder. Mol Psychiatry 23, 792–793 (2018). https://doi.org/10.1038/mp.2017.149

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