MITOL deletion in the brain impairs mitochondrial structure and ER tethering leading to oxidative stress
MITOL deletion in the brain impairs mitochondrial structure and ER tethering leading to oxidative stress
复制标题
DOI：
10.26508/lsa.201900308
复制
发表时间：
2019-08
影响因子：
4.4
通讯作者：
Shun Nagashima;Keisuke Takeda;N. Ohno;S. Ishido;Motohide Aoki;Y. Saitoh;Takumi Takada;Takeshi Tokuyama;Ayumu Sugiura;Toshifumi Fukuda;Nobuko Matsushita;R. Inatome;S. Yanagi
中科院分区：
文献类型：
--
作者：
Shun Nagashima;Keisuke Takeda;N. Ohno;S. Ishido;Motohide Aoki;Y. Saitoh;Takumi Takada;Takeshi Tokuyama;Ayumu Sugiura;Toshifumi Fukuda;Nobuko Matsushita;R. Inatome;S. Yanagi
小鼠脑中丝裂醇的缺失损害了线粒体的形态和内质网连接，导致氧化应激增强。这项研究表明线粒体的形态异常与发育障碍之间存在一定的关系。线粒体异常与发育障碍有关，尽管因果关系在很大程度上仍不清楚。在这里，我们报告了线粒体泛素连接酶mitol的缺失增加了神经元的氧化应激，导致了潜在的神经炎症，包括异常的星形胶质细胞增生和小胶质细胞的激活，这表明线粒体的异常可能会导致大脑中的炎症性疾病，如精神障碍。丝裂醇在线粒体动力学和内质网线粒体拴系中的作用促使我们在体内表征线粒体的三维结构。在丝裂醇缺乏的神经元中，我们观察到内质网与线粒体的接触部位显著减少，这可能导致磷脂转移的扰动，从而减少心磷脂的生物合成。我们还发现，由于丝裂醇的缺失，分枝的大线粒体消失。线粒体的这些形态异常导致脑内氧化应激增强，从而导致星形胶质细胞增生和小胶质细胞激活，部分导致行为异常。综上所述，内质网线粒体连接减少和线粒体过度分裂可能通过氧化应激引发神经炎症。
MITOL deletion in mouse brain impairs the morphology and ER tethering of mitochondria, resulting in enhanced oxidative stress. This study suggests a relationship between morphological abnormalities of mitochondria and developmental disorder. Mitochondrial abnormalities are associated with developmental disorders, although a causal relationship remains largely unknown. Here, we report that increased oxidative stress in neurons by deletion of mitochondrial ubiquitin ligase MITOL causes a potential neuroinflammation including aberrant astrogliosis and microglial activation, indicating that mitochondrial abnormalities might confer a risk for inflammatory diseases in brain such as psychiatric disorders. A role of MITOL in both mitochondrial dynamics and ER-mitochondria tethering prompted us to characterize three-dimensional structures of mitochondria in vivo. In MITOL-deficient neurons, we observed a significant reduction in the ER-mitochondria contact sites, which might lead to perturbation of phospholipids transfer, consequently reduce cardiolipin biogenesis. We also found that branched large mitochondria disappeared by deletion of MITOL. These morphological abnormalities of mitochondria resulted in enhanced oxidative stress in brain, which led to astrogliosis and microglial activation partly causing abnormal behavior. In conclusion, the reduced ER-mitochondria tethering and excessive mitochondrial fission may trigger neuroinflammation through oxidative stress.