Vawter MP, Tomita H, Meng F, Bolstad B, Li J, Evans S et al. Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders. Mol Psychiatry 11: 663-679

Department of Psychiatry, University of California, Irvine, USA.
Molecular Psychiatry (Impact Factor: 14.5). 08/2006; 11(7):615, 663-79. DOI: 10.1038/
Source: PubMed


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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    ABSTRACT: Major depressive disorder (MDD) is an important public health problem affecting 350 million people worldwide. After decades of study, the pathophysiology of MDD remains elusive, resulting in treatments that are only 30-60 % effective. This review summarizes the emerging evidence that implicates impaired mitochondrial bioenergetics as a basis for MDD. It is suggested that impaired mitochondrial bioenergetic function contributes to the pathophysiology of MDD via several potential pathways including: genetics/genomics, inflammation, oxidative stress, and alterations in neuroplasticity. A discussion of mitochondrial bioenergetic pathways that lead to MDD is provided. Evidence is reviewed regarding the mito-toxic or mito-protective impact of various antidepressant medications currently in use. Opportunities for further research on novel therapeutic approaches, including mitochondrial modulators, as stand-alone or adjunct therapy for reducing depression are suggested. In conclusion, while there is substantial evidence linking mitochondrial bioenergetics and MDD, there are currently no clear mitochondrial phenotypes or biomarkers to use as guides in targeting therapies beyond individuals with MDD and known mitochondrial disorders toward the general population of individuals with MDD. Further study is needed to develop these phenotypes and biomarkers, to identify therapeutic targets, and to test therapies aimed at improving mitochondrial function in individuals whose MDD is to some extent symptomatic of impaired mitochondrial bioenergetics.
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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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    ABSTRACT: As energy producers, mitochondria play a pivotal role in multiple cellular processes. Although several lines of evidence suggest that differential expression of mitochondrial respiratory complexes (MRCs) has a significant impact on mitochondrial function, the role of integrated MRCs in the whole coexpression network has yet to be revealed. In this study, we construct coexpression networks based on microarray datasets from different tissues and chemical treatments to explore the role of integrated MRCs in the coexpression network and the effects of different chemicals on the mitochondrial network. By grouping MRCs as one seed target, the hypergeometric distribution allowed us to identify genes that are significantly coexpress with whole MRCs. Coexpression among 46 MRC genes (approximately 78% of MRC genes tested) was significant in the normal tissue transcriptome dataset. These MRC genes are coexpressed with genes involved in the categories "muscle system process," "metabolic process," and "neurodegenerative disease pathways," whereas, in the chemically treated tissues, coexpression of these genes mostly disappeared. These results indicate that chemical stimuli alter the normal coexpression network of MRC genes. Taken together, the datasets obtained from the different coexpression networks are informative about mitochondrial biogenesis and should contribute to understanding the side effects of drugs on mitochondrial function.
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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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    ABSTRACT: Evidence supports the role for mitochondrial impairment in the pathophysiology of Bipolar Disorder (BD). BD has been associated with decreased mitochondrial electron transport chain activity and increased oxidative stress. Also, mitochondrial DNA (mtDNA) encodes mitochondrial electron transport chain proteins and has been associated with altered oxidative stress. Preclinical studies showed lithium treatment increasing mtDNA content, but no study has directly assessed mtDNA content in subjects with BD in vivo. Also, the effects of lithium treatment on mtDNA content have never been evaluated in humans. Leukocyte mtDNA content using with real time-PCR was evaluated in subjects with BD (n=23) in a depressive episode (≥18 in the 21-item Hamilton Depression Rating Scale) before and after 6-week lithium treatment versus healthy controls (n=24). mtDNA content showed no significant difference between subjects with BD at baseline and controls (p=0.46); also no difference was observed when comparing before and after lithium treatment. A trend for decreased mtDNA content was specifically observed in BD type I compared to controls and BD type II (p=0.05). Importantly, endpoint mtDNA copy number was significantly correlated with age. In younger, unmedicated and with shorter duration of illness, no change was observed in mtDNA copy number in subjects with BD. More studies with larger samples are warranted to evaluate mtDNA content changes in BD and its potential role as a treatment target, especially in BD type I and associated with aging.
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