Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia.
Several clinical, genetic and neuroimaging studies implicate mitochondrial dysfunction in the pathophysiology of bipolar disorder and schizophrenia. It has been reported that a mitochondrial DNA (mtDNA) deletion of 4,977 bp, known as the 'common deletion', is associated with both mental illnesses. A lack of normal age-related accumulation of this deletion in schizophrenia and increased occurrence of the common deletion in bipolar disorder have been reported. However, even in the affected bipolar samples, the levels of common deletion were relatively small, indicating that the common deletion did not play a pathophysiological role in respiratory function. We hypothesized that accumulation of multiple mtDNA deletions, rather than the common deletion alone, is involved in the pathophysiology of these two major mental disorders. To test this hypothesis, we assessed mtDNA deletion(s) by comparing the copy number of two regions in mtDNA -- ND1 and ND4 -- using real-time quantitative PCR in the frontal cortex of 84 subjects (30 control, 27 with bipolar disorder, and 27 with schizophrenia). We also assessed the relative amount of mtDNA vs. nuclear DNA and the expression level of DNA polymerase gamma (POLG), which is involved in replicating mtDNA. We observed no association between mtDNA deletions and the two major mental disorders in the frontal cortex, which did not support our hypothesis. We did, however, make the following observations, although they were not significant after Bonferroni correction: (1) the ratio of mtDNA to nuclear DNA was significantly higher in female patients with schizophrenia than in control females ( p =0.040) and (2) in bipolar disorder, the relative amount of mtDNA decreased with age ( p =0.016). furthermore, POLG expression was significantly up-regulated in bipolar disorder ( p =0.036). Our results suggest that abnormalities in the system maintaining replication of mtdna may underlie bipolar disorder and schizophrenia.
Kakiuchi
Chihiro
C
Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Hirosawa 2-1, Wako, Saitama, Japan. kakiuchi@brain.riken.jp
Ishiwata
Mizuho
M
Kametani
Mizue
M
Nelson
Cheryl
C
Iwamoto
Kazuya
K
Kato
Tadafumi
T
D000328:Adult; D000375:Aging / Q000502:physiology; D001714:Bipolar Disorder / Q000235:genetics*; D002467:Cell Nucleus / Q000235:genetics; D002540:Cerebral Cortex / Q000737:chemistry; D041321:Chromosomes, Human, X / Q000235:genetics; D000074002:DNA Polymerase gamma; D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics*; D017384:Sequence Deletion; D012727:Sex Characteristics
D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase