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

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 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.

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

“…This prior analysis combined 10 brain regions and showed there was a decrease in the common deletion in SZ compared to controls [13]; however, this analysis was not conducted herein since we analyzed a single brain region. We also show that female subjects have a 60% increase in the accumulation of the common deletion in the PFC consistent with previous reports in DLPFC showing increased common deletion levels in females compared to males [10,31,34]. The increase in the common deletion in female PFC could indicate that there might be higher levels of reactive oxygen produced due to more common deletion in mtDNA, while the reverse direction of cause could also be consistent.…”

Quantitative analysis of mitochondrial DNA 4977-bp deletion in sporadic breast cancer and benign breast diseases

“…Furthermore, these PCR methods use an endpoint determination that may not be truly quantitative because of plateau effects (21). There have been some reports demonstrating the advantages of using the real-time PCR method and its potential clinical value for the mtDNA 4977 mutation (8,(18)(19)(20)22). However, only two of these reports used the standard curve method, which is believed to be more reliable and sensitive (18,19).…”

Mitochondrial involvement in psychiatric disorders

“…However, these authors also failed to observe age-related accumulation of the common deletion in SZ (94), which is a feature of normal control brains (95). Kakiuchi et al (2005) (96) also failed to see an increase in the common deletion in subjects with BPD or SZ, or age-related increases in levels of the deletion. However, the lack of an increase in age-related deletions may be related to the overall younger age of the subjects, as age-matched controls apparently did not display age-related increases in deletion (96), or perhaps the methodology.…”

“…Kakiuchi et al (2005) (96) also failed to see an increase in the common deletion in subjects with BPD or SZ, or age-related increases in levels of the deletion. However, the lack of an increase in age-related deletions may be related to the overall younger age of the subjects, as age-matched controls apparently did not display age-related increases in deletion (96), or perhaps the methodology. Sabunciyan et al (2007) (93) reported that antidepressant and alcohol use in bipolar patients and first-generation typical antipsychotics in SZ were correlated to the level of common deletion.…”