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

Department of Psychiatry, University of California, Irvine, USA.
Molecular Psychiatry (Impact Factor: 15.15). 08/2006; 11(7):615, 663-79. DOI: 10.1038/sj.mp.4001830
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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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    • "Postmortem research is potentially confounded by changes in the near death or agonal period and in the postmortem period prior to either tissue freezing or fixation. However, brain tissue pH, postmortem interval prior to tissue freezing or fixation, among other factors have been used in post-hoc statistical analyses in an attempt to control for agonal and postmortem effects (Vawter et al. 2006). Furthermore, many individuals had been taking psychiatric medications around the time of death, and therefore drug effects can also only be controlled for using post hoc analyses. "
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    • "One possible explanation for these changes in coexpression in response to chemical treatment is that these compounds directly or indirectly influence MRC gene expression. Indeed, differential expression of mitochondrial genes has been induced by manipulating the agonal-pH state and through drug treatment [40] [41]. Furthermore, some compounds might modulate cellular redox levels or dissipate the mitochondrial membrane gradient by facilitating anion flux across the mitochondrial inner membrane, as suggested by Toogood [42], resulting in remodeling of the coexpression network. "
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    • "The present results are in accordance with three studies in BD post-mortem brains which showed no alteration in mtDNA content (Kakiuchi et al. 2005, Sabunciyan et al. 2007, Torrell et al. 2013). In contrast with our findings, one study found mtDNA content slightly increased in post-mortem BD subjects (Vawter et al., 2006). The mtDNA content in peripheral cells may reflect similar mtDNA content in other targets (such as brain) involved different diseases (Malik and Czajka, 2012), which reinforces the validity of our findings in leukocytes. "
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