Kato Tadafumi
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Hirosawa 2-1, Wako, Saitama, Japan.
Cell Calcium. 2008 Jul;44(1):92-102. doi: 10.1016/j.ceca.2007.11.005. Epub 2008 Jan 4.
Altered intracellular calcium levels are a consistent finding in studies of bipolar disorder, and recent studies point to the role of mitochondrial dysfunction, leading to the possibility that mitochondrial calcium dysregulation is involved in the pathophysiology of the disease. Although the mitochondrion is a key organelle for calcium accumulation, initial calcium signaling studies in bipolar disorder did not focus on the role of mitochondria. Later, neuroimaging and molecular genetic studies suggested the possibility that altered mitochondrial calcium regulation due to mitochondrial DNA (mtDNA) polymorphisms/mutations might be involved in the pathophysiology of bipolar disorder. Recent studies show that certain mtDNA polymorphisms alter mitochondrial calcium levels. Mutant mtDNA polymerase (Polg) transgenic mice carrying mtDNA mutations in forebrain cells show an increased calcium uptake rate in isolated mitochondria. This was found to be mediated by downregulation of cyclophilin D, a component of the mitochondrial permeability transition pore. In addition, agonist-stimulated calcium response is attenuated in hippocampal neurons of these transgenic mice. The finding that mtDNA polymorphisms and mutations affect mitochondrial calcium regulation supports the idea that mitochondrial calcium dysregulation may be involved in the pathophysiology of bipolar disorder. In this review, the history and recent findings of studies elucidating the role of mitochondrial calcium signaling in bipolar disorder are summarized.
细胞内钙水平改变是双相情感障碍研究中的一个一致发现，最近的研究指出了线粒体功能障碍的作用，这使得线粒体钙调节异常可能参与该疾病的病理生理学过程。尽管线粒体是钙积累的关键细胞器，但双相情感障碍最初的钙信号研究并未关注线粒体的作用。后来，神经影像学和分子遗传学研究表明，由于线粒体DNA（mtDNA）多态性/突变导致的线粒体钙调节改变可能参与双相情感障碍的病理生理学过程。最近的研究表明，某些mtDNA多态性会改变线粒体钙水平。在前脑细胞中携带mtDNA突变的突变型mtDNA聚合酶（Polg）转基因小鼠，其分离的线粒体中钙摄取率增加。这被发现是由线粒体通透性转换孔的一个成分亲环蛋白D的下调介导的。此外，这些转基因小鼠海马神经元中激动剂刺激的钙反应减弱。mtDNA多态性和突变影响线粒体钙调节的这一发现支持了线粒体钙调节异常可能参与双相情感障碍病理生理学过程的观点。在这篇综述中，总结了阐明线粒体钙信号在双相情感障碍中作用的研究的历史和最新发现。
