Kriebel Martin, Ebel Julia, Battke Florian, Griesbach Stefan, Volkmer Hansjürgen
Department of Molecular Biology and Neurobiology, NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
CeGaT GmbH, Tübingen, Germany.
Front Mol Neurosci. 2020 Mar 24;13:43. doi: 10.3389/fnmol.2020.00043. eCollection 2020.
Age-related impairment of mitochondrial function may negatively impact energy-demanding processes such as synaptic transmission thereby triggering cognitive decline and processes of neurodegeneration. Here, we present a novel model for age-related mitochondrial impairment based on partial inhibition of cytochrome c oxidase subunit 4 (Cox4) of complex IV of the respiratory chain. miRNA-mediated knockdown of Cox4 correlated with a marked reduction in excitatory and inhibitory synaptic marker densities and as well as an impairment of neuronal network activity in primary neuronal cultures. Transcriptome analysis identified the deregulation of gene clusters, which link induced mitochondrial perturbation to impaired synaptic function and plasticity as well as processes of aging. In conclusion, the model of Cox4 deficiency reflects aspects of age-related dementia and might, therefore, serve as a novel test system for drug development.
与年龄相关的线粒体功能损害可能会对能量需求过程产生负面影响，如突触传递，从而引发认知衰退和神经退行性变过程。在此，我们基于对呼吸链复合物IV的细胞色素c氧化酶亚基4（Cox4）的部分抑制，提出了一种与年龄相关的线粒体损害的新模型。miRNA介导的Cox4基因敲低与原代神经元培养物中兴奋性和抑制性突触标志物密度的显著降低以及神经网络活动的损害相关。转录组分析确定了基因簇的失调，这些基因簇将诱导的线粒体扰动与受损的突触功能和可塑性以及衰老过程联系起来。总之，Cox4缺陷模型反映了与年龄相关的痴呆症的各个方面，因此可能作为药物开发的新型测试系统。
