Department of Organ Anatomy, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
Division of Animal Metabolism and Nutrition, Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization, Tsukuba, 305-0901, Japan.
Sci Rep. 2021 May 26;11(1):10969. doi: 10.1038/s41598-021-90127-4.
Altered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation in human is associated with Leigh syndrome. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons, and GFAP-positive astrocytes in WT mouse hippocampus, we found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Although there was no change in the number of NeuN positive neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was significantly decreased. To investigate the detailed mechanism, we silenced Ndufs4 in Neuro-2a cells and we observed shorter neurite lengths with decreased expression of synaptophysin. Furthermore, western blot analysis for phosphorylated extracellular regulated kinase (pERK) revealed that Ndufs4 silencing decreases the activity of ERK signalling. These results suggest that Ndufs4-modulated mitochondrial activity may be involved in neuroplasticity via regulating synaptophysin expression.
线粒体呼吸链功能改变与许多神经退行性疾病有关。NADH 脱氢酶（泛醌）Fe-S 蛋白 4（Ndufs4）是线粒体复合物 I 的亚基之一，其在人类中的突变与 Leigh 综合征有关。然而，Ndufs4 在神经元功能中的分子生物学作用知之甚少。在这项研究中，在 WT 小鼠海马体的 NeuN 阳性神经元和 GFAP 阳性星形胶质细胞中证实了 Ndufs4 的表达后，我们发现 Ndufs4-KO 小鼠海马体的线粒体呼吸明显减少。尽管 Ndufs4-KO 海马体中 NeuN 阳性神经元的数量没有变化，但突触小泡蛋白（一种突触前蛋白）的表达显著下降。为了研究详细的机制，我们在 Neuro-2a 细胞中沉默了 Ndufs4，我们观察到神经突长度变短，突触小泡蛋白表达减少。此外，磷酸化细胞外调节激酶（pERK）的 Western blot 分析表明，Ndufs4 沉默会降低 ERK 信号的活性。这些结果表明，Ndufs4 调节的线粒体活性可能通过调节突触小泡蛋白的表达参与神经可塑性。
