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Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

Molecular Psychiatry volume 11, pages 663–679 (2006)Cite this article

Abstract

Mitochondrial defects in gene expression have been implicated in the pathophysiology of bipolar disorder and schizophrenia. We have now contrasted control brains with low pH versus high pH and showed that 28% of genes in mitochondrial-related pathways meet criteria for differential expression. A majority of genes in the mitochondrial, chaperone and proteasome pathways of nuclear DNA-encoded gene expression were decreased with decreased brain pH, whereas a majority of genes in the apoptotic and reactive oxygen stress pathways showed an increased gene expression with a decreased brain pH. There was a significant increase in mitochondrial DNA copy number and mitochondrial DNA gene expression with increased agonal duration. To minimize effects of agonal-pH state on mood disorder comparisons, two classic approaches were used, removing all subjects with low pH and agonal factors from analysis, or grouping low and high pH as a separate variable. Three groups of potential candidate genes emerged that may be mood disorder related: (a) genes that showed no sensitivity to pH but were differentially expressed in bipolar disorder or major depressive disorder; (b) genes that were altered by agonal-pH in one direction but altered in mood disorder in the opposite direction to agonal-pH and (c) genes with agonal-pH sensitivity that displayed the same direction of changes in mood disorder. Genes from these categories such as NR4A1 and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders.

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Acknowledgements

We appreciate the assistance of Preston Cartagena, PsyD and Richard Stein, PhD for their contributions to postmortem clinical characterization of subjects. We acknowledge Kathleen Burke as well as Jacque Berndt and the investigators and medical examiners at the Orange County Coroners Office for procurement of brain tissue. We also appreciate the technical contributions of Kevin Overman, Sharon Burke, Xiaohong Fan and Phong Nguyen. F Warren Lovell, MD, performed a neuropathological evaluation of the postmortem brains. Tissue specimens were processed and stored at the Human Brain and Spinal Fluid Resource Center, Veteran's Medical Center, Los Angeles under the direction of Wallace W Tourtellotte, MD, PhD This project is supported by the NIMH Conte Center Grant P50 MH60398, Pritzker Family Philanthropic Fund, William Lion Penzner Foundation (UCI), Della Martin Foundation (UCI), NIMH Grant #MH54844 (EGJ), WM Keck Foundation (EGJ) and the NIMH Program Project MH42251 (SJW and HA). The authors are members of a Conte Center supported by the NIMH and members of the Pritzker Neuropsychiatric Disorders Research Consortium, which is supported by the Pritzker Family Philanthropic Fund. A shared intellectual property agreement exists between the Pritzker Family Philanthropic Fund and all the universities involved, in order to encourage the development of appropriate findings for research and clinical applications. The academic and philanthropic entities involved in this Consortium are jointly filing patent applications related to the present findings.

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Authors and Affiliations

  1. Department of Psychiatry, University of California, Irvine, CA, USA

    M P Vawter, H Tomita, M Atz, L Shao, D M Walsh & W E Bunney

  2. Mental Health Research Institute, University of Michigan, Ann Arbor, MI, USA

    F Meng, S Evans, M Burmeister, S J Watson & H Akil

  3. Biostatistics, University of California, Berkeley, CA, USA

    B Bolstad & T Speed

  4. Stanford Human Genome Center, Stanford University, Palo Alto, CA, USA

    J Li & R Myers

  5. Center for Neuroscience, University of California, Davis, CA, USA

    P Choudary & E G Jones

  6. University of Hawaii, John A. Burns School of Medicine, Honolulu, HI, USA

    C Neal

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Vawter, M., Tomita, H., Meng, F. et al. Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders. Mol Psychiatry 11, 663–679 (2006). https://doi.org/10.1038/sj.mp.4001830

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INTERN 1
Project 2