Abnormal Ca2+ dynamics in transgenic mice with neuron-specific mitochondrial DNA defects
Abnormal Ca2+ dynamics in transgenic mice with neuron-specific mitochondrial DNA defects
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DOI：
10.1523/jneurosci.3933-06.2006
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发表时间：
2006-11-22
影响因子：
5.3
通讯作者：
Kato, Tadafumi
中科院分区：
文献类型：
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作者：
Kubota, Mie;Kasahara, Takaoki;Kato, Tadafumi
线粒体DNA（mitochondrial DNA，mtDNA）的维持依赖于核编码蛋白如mtDNA聚合酶（polymerase，POLG），其突变与mtDNA缺陷引起的疾病有关，包括突变和缺失。双相情感障碍（bipolar disorder，BD）患者存在线粒体DNA和细胞内Ca ~（2+）（[Ca ~（2+）]（i））稳态的缺陷。为了了解线粒体DNA缺陷与BD的相关性，我们研究了转基因（Tg）小鼠，其中突变型POLG（mutPOLG）在神经元中特异性表达。mtDNA缺陷在mutPOLG Tg小鼠的脑中以年龄依赖性的方式积累，并且突变小鼠表现出BD样行为。然而，异常的分子和细胞基础尚未阐明。在这项研究中，我们研究了钙调节分离线粒体和[Ca 2 +]（i）在神经元的mutPOLG转基因小鼠。突变小鼠的线粒体更迅速地螯合Ca 2+，而线粒体的Ca 2+保留能力和膜电位（Ca 2+摄取的驱动力）不受影响。为了阐明改变的Ca 2+摄取的分子机制，我们进行了DNA微阵列分析，发现亲环素D（CyP-D）的表达，渗透性转换孔的一个组成部分，下调mutPOLG Tg小鼠的大脑。CyP-D的抑制剂环孢素A模拟突变小鼠中增强的Ca 2+摄取。此外，G蛋白偶联受体介导的[Ca 2 +]（i）增加在突变小鼠的海马神经元中减弱。这些发现表明，线粒体DNA缺陷通过CyP-D下调导致Ca 2+摄取率增强并改变[Ca 2 +]（i）动力学，这可能参与BD的发病机制。
Maintenance of mitochondrial DNA (mtDNA) depends on nuclear-encoded proteins such as mtDNA polymerase (POLG), whose mutations are involved in the diseases caused by mtDNA defects including mutation and deletion. The defects in mtDNA and in intracellular Ca2+ ([Ca2+](i)) homeostasis have been reported in bipolar disorder (BD). To understand the relevance of the mtDNA defects to BD, we studied transgenic (Tg) mice in which mutant POLG (mutPOLG) was expressed specifically in neurons. mtDNA defects were accumulated in the brains of mutPOLG Tg mice in an age-dependent manner and the mutant mice showed BD-like behavior. However, the molecular and cellular basis for the abnormalities has not been clarified. In this study, we investigated Ca2+ regulation by isolated mitochondria and [Ca2+](i) dynamics in the neurons of mutPOLG Tg mice. Mitochondria from the mutant mice sequestered Ca2+ more rapidly, whereas Ca2+ retention capacity and membrane potential, a driving force of Ca2+ uptake, of mitochondria were unaffected. To elucidate the molecular mechanism of the altered Ca2+ uptake, we performed DNA microarray analysis and found that the expression of cyclophilin D (CyP-D), a component of the permeability transition pore, was downregulated in the brains of mutPOLG Tg mice. Cyclosporin A, an inhibitor of CyP-D, mimicked the enhanced Ca2+ uptake in mutant mice. Furthermore, G-protein-coupled receptor-mediated [Ca2+](i) increase was attenuated in hippocampal neurons of the mutant mice. These findings suggest that mtDNA defects lead to enhancement of Ca2+ uptake rate via CyP-D downregulation and alter [Ca2+](i) dynamics, which may be involved in the pathogenesis of BD.