Molecular Evidence for Mitochondrial Dysfunction in Bipolar Disorder

Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
Archives of General Psychiatry (Impact Factor: 14.48). 04/2004; 61(3):300-8. DOI: 10.1001/archpsyc.61.3.300
Source: PubMed


The disease mechanism of bipolar disorder remains unknown. Recent studies have provided evidence for abnormal gene expression in bipolar disorder.
To determine the expression of 12558 nuclear genes in the human hippocampus in healthy control subjects and those with bipolar disorder or schizophrenia.
We used gene arrays to study messenger RNA expression. Data were verified with a real-time quantitative polymerase chain reaction assay.
We studied 10 healthy control subjects, 9 subjects with bipolar disorder, and 8 subjects with schizophrenia.
The expression of nuclear messenger RNA coding for mitochondrial proteins was significantly decreased in the hippocampus in subjects with bipolar disorder but not in those with schizophrenia. Subjects with bipolar disorder were characterized by a pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation and the adenosine triphosphate-dependent process of proteasome degradation.
These findings point toward a widespread dysregulation of mitochondrial energy metabolism and downstream deficits of adenosine triphosphate-dependent processes in bipolar disorder.

Download full-text


Available from: Christine Konradi, Mar 31, 2014
  • Source
    • "A recent study (Torrell et al., 2013) observed higher levels of CDel in occipital cortex of MDDs and SZ compared to BD and controls, however, their results were not significant and they did not control for age, which is highly correlated with levels of the CDel in many prior studies of brain and other metabolically active tissues. Multiple lines of evidence (transcriptomic, proteomic, neuroimaging, in vitro, peripheral tissue, genetic, and animal studies) implicates mitochondrial dysfunction in mood disorders (Kato and Kato, 2000; Bezchlibnyk et al., 2001; Konradi et al., 2004; Choudary et al., 2005; Iwamoto et al., 2005; Washizuka et al., 2005; Ryan et al., 2006; Sun et al., 2006; Vawter et al., 2006; Kato et al., 2007; Shao et al., 2008; Rao et al., 2010). Recent studies have provided evidence that mtDNA sequence variants, and subsequent mitochondrial dysfunction, are associated with an increased incidence of depression (Gardner et al., 2003; Burnett et al., 2005; Fattal et al., 2006; Vawter et al., 2006; Gardner and Boles, 2008, 2011; Shao et al., 2008; Rollins et al., 2009; Anglin et al., 2012; Inczedy-Farkas et al., 2012), suggesting that Schizophrenia Research 159 (2014) 370–375 ⁎ Corresponding author at: "
    [Show abstract] [Hide abstract]
    ABSTRACT: Large deletions in mitochondrial DNA (mtDNA) can occur during or result from oxidative stress leading to a vicious cycle that increases reactive oxygen species (ROS) damage and decreases mitochondrial function, thereby causing further oxidative stress. The objective of this study was to determine if disease specific brain differences of the somatic mtDNA common deletion (4977 bp) could be observed in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) compared to a control group.
    Schizophrenia Research 11/2014; 159(2-3):370-375. DOI:10.1016/j.schres.2014.08.026 · 3.92 Impact Factor
  • Source
    • "Also, the use of peripheral cells (instead of postmortem brain tissue) or the relatively small sample size could have prevented us from finding significant differences between patients and controls in ETC complexes activities. Previous postmortem studies in BD pointed out to a decrease in complex I activity (Andreazza et al. 2010) and ETC complexes subunit proteins expression (Konradi et al. 2004; Sun et al. 2006). In addition, complex I subunit protein expression was decreased in peripheral cells of BD patients (Washizuka et al. 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Different lines of evidence suggest that mitochondrial dysfunction may be implicated in bipolar disorder (BD) pathophysiology. Mitochondrial electron transport chain (ETC) is a key target to evaluate mitochondrial function, but its activity has never been assessed in unmedicated BD or during mood episodes. Also, lithium has been shown to increase ETC gene expression/activity in preclinical models and in postmortem brains of BD subjects, but to date, no study has evaluated lithium's direct effects on ETC activity in vivo.
    Psychopharmacology 06/2014; 232(1). DOI:10.1007/s00213-014-3655-6 · 3.88 Impact Factor
  • Source
    • "ME2 is a mitochondrial enzyme involved in neuronal glucose metabolism and in the synthesis of 2 key neurotransmitters, namely, GABA and glutamate.30) These findings are consistent with the reports that mitochondrial enzyme dysfunction plays a role in the pathophysiology of psychotic disorders.44,45,46,47,48,49) Previous studies conducted in the Central Valley of Costa Rica (CVCR; one using samples of severe bipolar disorder, the other using subjects primarily diagnosed with schizophrenia) showed evidences for the existence of LD between the phenotypes of schizophrenia and bipolar disorders and the 18q21,22,50) 2.41 cM region (2.7 Mb) spanning from D18S450 to D18S474. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective It was previously suggested that the malic enzyme 2 (ME2) as the candidate gene for psychosis in fine mapping of chromosome 18q21. Chromosome 18q21 is also one of the possible regions that can contribute to addiction. Methods We performed a pilot study for discovering candidate gene of chromosome 18q21 in the methamphetamine abusers for elucidating the candidate gene for methamphetamine addiction leading to psychosis. We have selected 30 unrelated controls (16 males, 14 females; age=59.8±10.4) and 37 male methamphetamine abusers (age=43.3±7.8). We analyzed 20 single nucleotide polymorphisms (SNPs) of 7 neuronal genes in chromosome 18q21 for DNA samples that was checked for the data quality and genotype error. The association between the case-control status and each individual SNP was measured using multiple logistic regression models (adjusting for age and sex as covariates). And we controlled false discovery rate (FDR) to deal with multiple testing problem. Results We found 3 significant SNPs of 2 genes in chromosome 18q21 (p-value<0.05; adjusting for age as covariate) in methamphetamine abusers compared to controls. We also found 2 significant SNPs of 1 gene (p-value<0.05; adjusting for age and sex as covariates) (rs3794899, rs3794901:MAPK4). Two SNPs in MAPK4 gene were significant in both statistical groups. Conclusion MAPK4, the gene for mitogen-activated protein kinase 4, is one of the final 6 candidate genes including ME2 in 18q12-21 in our previous finemapping for psychosis. Our results suggest that MAPK4 can be a candidate gene that contribute to the methamphetamine addiction leading to psychosis.
    Clinical Psychopharmacology and Neuroscience 04/2014; 12(1):54-64. DOI:10.9758/cpn.2014.12.1.54
Show more