m.3243A>G 线粒体 DNA 突变在体外人血脑屏障模型中具有致病性。
The m.3243A>G mtDNA mutation is pathogenic in an in vitro model of the human blood brain barrier.
机构信息
Department of Neurology, Columbia University Medical Center, New York, NY 10032, United States.
出版信息
Mitochondrion. 2009 Nov;9(6):463-70. doi: 10.1016/j.mito.2009.08.006. Epub 2009 Aug 12.
Abstract
MELAS is a common mitochondrial disease frequently associated with the m.3243A>G point mutation in the tRNA(Leu(UUR)) of mitochondrial DNA and characterized by stroke-like episodes with vasogenic edema and lactic acidosis. The pathogenic mechanism of stroke and brain edema is not known. Alterations in the blood brain barrier (BBB) caused by respiratory chain defects in the cortical microvessels could explain the pathogenesis. To test this hypothesis we developed a tissue culture model of the human BBB. The MELAS mutation was introduced into immortalized brain capillary endothelial cells and astrocytes. Respiratory chain activity and transendothelial electrical resistance, TEER was measured. Severe defects of respiratory chain complex I and IV activities, and a moderate deficiency of complex II activity in cells harboring the MELAS mutation were associated with low TEER, indicating that the integrity of the BBB was compromised. These data support our hypothesis that respiratory chain defects in the components of the BBB cause changes in permeability.
摘要
MELAS 是一种常见的线粒体疾病，常与线粒体 DNA 的 tRNA（亮氨酸（UUR））中的 m.3243A>G 点突变相关，其特征是血管源性水肿和乳酸性酸中毒伴发类似中风的发作。中风和脑水肿的发病机制尚不清楚。皮质微血管呼吸链缺陷引起的血脑屏障（BBB）改变可以解释其发病机制。为了验证这一假说，我们建立了人 BBB 的组织培养模型。将 MELAS 突变引入永生化脑毛细血管内皮细胞和星形胶质细胞。测量呼吸链活性和跨内皮电阻（TEER）。携带 MELAS 突变的细胞中呼吸链复合物 I 和 IV 活性严重缺陷，以及复合物 II 活性中度缺乏与 TEER 降低相关，表明 BBB 的完整性受到损害。这些数据支持我们的假说，即 BBB 成分中的呼吸链缺陷导致通透性改变。
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