Mitochondrial Dysfunction in Astrocytes Impairs the Generation of Reactive Astrocytes and Enhances Neuronal Cell Death in the Cortex Upon Photothrombotic Lesion
Mitochondrial Dysfunction in Astrocytes Impairs the Generation of Reactive Astrocytes and Enhances Neuronal Cell Death in the Cortex Upon Photothrombotic Lesion
复制标题
DOI：
10.3389/fnmol.2019.00040
复制
发表时间：
2019-02-22
影响因子：
4.8
通讯作者：
Beckervordersandforth, Ruth
中科院分区：
文献类型：
--
作者：
Fiebig, Christian;Keiner, Silke;Beckervordersandforth, Ruth
线粒体是调节细胞代谢状态的关键细胞器。在大脑中，线粒体氧化代谢是神经元产生ATP的主要机制。虽然已经确定神经元的功能高度依赖于线粒体代谢，但对星形胶质细胞的功能如何依赖于线粒体却知之甚少。在这项研究中，我们研究了在生理和损伤条件下星形胶质细胞是否需要功能性线粒体电子传递链（ETC）和氧化磷酸化（oxPhos）。通过免疫组化，我们发现星形胶质细胞在体内表达ETC和oxPhos复合物的成分。线粒体转录因子A （Tfam）的条件缺失对线粒体转录的遗传抑制导致ETC和oxPhos活性的功能失调，星形胶质细胞中线粒体异常肿胀表明了这一点。线粒体功能障碍不影响星形胶质细胞的存活，但在生理条件下引起皮层反应性胶质细胞增生。光化学引发的血栓引起的缺血性中风导致病变周围反应性星形胶质细胞形成高灌注线粒体网络。重要的是，线粒体功能障碍显著减少了新星形胶质细胞的产生，增加了病变周围区域的神经元细胞死亡。这些结果表明，在损伤条件下，星形胶质细胞的增殖和神经保护需要功能性ETC和oxPhos机制。
Mitochondria are key organelles in regulating the metabolic state of a cell. In the brain, mitochondrial oxidative metabolism is the prevailing mechanism for neurons to generate ATP. While it is firmly established that neuronal function is highly dependent on mitochondrial metabolism, it is less well-understood how astrocytes function rely on mitochondria. In this study, we investigate if astrocytes require a functional mitochondrial electron transport chain (ETC) and oxidative phosphorylation (oxPhos) under physiological and injury conditions. By immunohistochemistry we show that astrocytes expressed components of the ETC and oxPhos complexes in vivo. Genetic inhibition of mitochondrial transcription by conditional deletion of mitochondrial transcription factor A (Tfam) led to dysfunctional ETC and oxPhos activity, as indicated by aberrant mitochondrial swelling in astrocytes. Mitochondrial dysfunction did not impair survival of astrocytes, but caused a reactive gliosis in the cortex under physiological conditions. Photochemically initiated thrombosis induced ischemic stroke led to formation of hyperfused mitochondrial networks in reactive astrocytes of the perilesional area. Importantly, mitochondrial dysfunction significantly reduced the generation of new astrocytes and increased neuronal cell death in the perilesional area. These results indicate that astrocytes require a functional ETC and oxPhos machinery for proliferation and neuroprotection under injury conditions.