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

Mol Psychiatry. 2006 Jul;11(7):615, 663-79. doi: 10.1038/sj.mp.4001830. Epub 2006 Apr 25.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents / pharmacology
  • Apoptosis / genetics
  • Bipolar Disorder / drug therapy
  • Bipolar Disorder / genetics
  • Bipolar Disorder / metabolism*
  • Bipolar Disorder / pathology
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Death*
  • Depressive Disorder / genetics
  • Depressive Disorder / metabolism*
  • Depressive Disorder / pathology
  • Female
  • Gene Dosage
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Gyrus Cinguli / drug effects
  • Gyrus Cinguli / metabolism
  • Gyrus Cinguli / pathology
  • Humans
  • Hydrogen-Ion Concentration*
  • In Situ Hybridization
  • Lithium / pharmacology
  • Male
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Molecular Chaperones / biosynthesis
  • Molecular Chaperones / genetics
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics*
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Oxidative Stress / genetics
  • Polymerase Chain Reaction
  • Postmortem Changes
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Serotonin Uptake Inhibitors / pharmacology
  • Time Factors

Substances

  • Antidepressive Agents
  • DNA, Mitochondrial
  • LRPPRC protein, human
  • Molecular Chaperones
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Serotonin Uptake Inhibitors
  • Lithium
  • Proteasome Endopeptidase Complex