Kakiuchi Chihiro, Ishiwata Mizuho, Kametani Mizue, Nelson Cheryl, Iwamoto Kazuya, Kato Tadafumi
Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Hirosawa 2-1, Wako, Saitama, Japan.
Int J Neuropsychopharmacol. 2005 Dec;8(4):515-22. doi: 10.1017/S1461145705005213.
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.
多项临床、遗传学和神经影像学研究表明，线粒体功能障碍与双相情感障碍和精神分裂症的病理生理学有关。据报道，一种4977bp的线粒体DNA（mtDNA）缺失，即所谓的“常见缺失”，与这两种精神疾病都有关联。有报道称，精神分裂症患者中这种缺失缺乏与年龄相关的正常积累，而双相情感障碍患者中常见缺失的发生率增加。然而，即使在受影响的双相情感障碍样本中，常见缺失的水平也相对较低，这表明常见缺失在呼吸功能中并未发挥病理生理作用。我们推测，多种mtDNA缺失的积累，而非仅常见缺失，参与了这两种主要精神障碍的病理生理学过程。为了验证这一假设，我们通过实时定量PCR比较了84名受试者（30名对照、27名双相情感障碍患者和27名精神分裂症患者）额叶皮质中mtDNA的两个区域——ND1和ND4——的拷贝数，以评估mtDNA缺失情况。我们还评估了mtDNA与核DNA的相对量以及参与mtDNA复制的DNA聚合酶γ（POLG）的表达水平。我们在额叶皮质中未观察到mtDNA缺失与这两种主要精神障碍之间的关联，这并不支持我们的假设。然而，我们确实有以下观察结果，尽管在Bonferroni校正后不显著：（1）精神分裂症女性患者中mtDNA与核DNA的比率显著高于对照女性（p = 0.040）；（2）在双相情感障碍中，mtDNA的相对量随年龄下降（p = 0.016）。此外，双相情感障碍中POLG表达显著上调（p = 0.036）。我们的结果表明，维持mtDNA复制的系统异常可能是双相情感障碍和精神分裂症的基础。
