PDF(Pubmed)
Abstract：
Astrocytes display context-specific diversity in their functions and respond to noxious stimuli between brain regions. Astrocytic mitochondria have emerged as key players in governing astrocytic functional heterogeneity, given their ability to dynamically adapt their morphology to regional demands on ATP generation and Ca2+ buffering functions. Although there is reciprocal regulation between mitochondrial dynamics and mitochondrial Ca2+ signaling in astrocytes, the extent of this regulation in astrocytes from different brain regions remains unexplored. Brain-wide, experimentally induced mitochondrial DNA (mtDNA) loss in astrocytes showed that mtDNA integrity is critical for astrocyte function, however, possible diverse responses to this noxious stimulus between brain areas were not reported in these experiments. To selectively damage mtDNA in astrocytes in a brain-region-specific manner, we developed a novel adeno-associated virus (AAV)-based tool, Mito-PstI expressing the restriction enzyme PstI, specifically in astrocytic mitochondria. Here, we applied Mito-PstI to two brain regions, the dorsolateral striatum and dentate gyrus, and we show that Mito-PstI induces astrocytic mtDNA loss in vivo, but with remarkable brain-region-dependent differences on mitochondrial dynamics, Ca2+ fluxes, and astrocytic and microglial reactivity. Thus, AAV-Mito-PstI is a novel tool to explore the relationship between astrocytic mitochondrial network dynamics and astrocytic mitochondrial Ca2+ signaling in a brain-region-selective manner.
摘要：
星形胶质细胞在其功能上表现出特定于环境的多样性，并对大脑区域之间的有害刺激做出反应。星形细胞线粒体已成为控制星形细胞功能异质性的关键参与者，鉴于它们能够动态调整其形态以适应ATP生成和Ca2缓冲功能的区域需求。尽管在星形胶质细胞中线粒体动力学和线粒体Ca2+信号之间存在相互调节,来自不同大脑区域的星形胶质细胞中这种调节的程度仍未被研究。全脑，实验诱导的线粒体DNA（mtDNA）在星形胶质细胞的损失表明，mtDNA完整性是星形胶质细胞功能的关键，然而,在这些实验中没有报道大脑区域之间对这种有害刺激的可能不同反应。以脑区域特异性方式选择性损伤星形胶质细胞中的mtDNA，我们开发了一种新的基于腺相关病毒（AAV）的工具，Mito-PstI表达限制酶PstI,特别是星形细胞线粒体。这里,我们将Mito-PstI应用于两个大脑区域，背外侧纹状体和齿状回，我们显示Mito-PstI在体内诱导星形细胞mtDNA丢失，但是在线粒体动力学上存在显著的大脑区域依赖性差异，Ca2+通量，星形胶质细胞和小胶质细胞反应性。因此，AAV-Mito-PstI是一种以脑区选择性方式探索星形细胞线粒体网络动力学与星形细胞线粒体Ca2信号传导之间关系的新工具。
