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

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.

Figure 1

In situ hybridization for leucine-rich PPR-motif containing (LRPPRC) mRNA in cerebellum. Representative autoradiographs show the pattern of In situ hybridization labeling across three different agonal factor scores. Several poor quality sections were eliminated from analysis (Figures 1b and 1c). (a) ISHH images of LRPPRC expression in control and bipolar disorder (BPD). (b) Controls with agonal factors showed a 36% reduction in LRPPRC compared to controls with zero agonal factors (P = 0.011) in cerebellum and a similar effect was seen across the cortical regions. The optical density (OD) was adjusted for radioactive standards (nC_i/g) included on the film and then multiplied by the area that was quantified transforming the relative OD to a range of 20 000–100 000 arbitrary units. The numbers of subjects used for quantitation are shown in each bar. (c) The BPD cases without agonal factors show increased LRPPRC by ISHH compared to controls without agonal factors (P = 0.001) and compared to major depressive disorder (MDD) subjects (P = 0.02) without agonal factors in the DLPFC. The numbers of subjects are shown in each bar.