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Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia

Chihiro Kakiuchi, Mizuho Ishiwata, Mizue Kametani, Cheryl Nelson, Kazuya Iwamoto, Tadafumi Kato
DOI: http://dx.doi.org/10.1017/S1461145705005213 515-522 First published online: 1 December 2005

Abstract

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 4977 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.

Key words
  • Bipolar disorder
  • deletions
  • frontal cortex
  • mitochondrial DNA
  • schizophrenia