Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Molecular and Integrative Biosciences Research Program, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Neurobiol Dis. 2020 Jul;141:104940. doi: 10.1016/j.nbd.2020.104940. Epub 2020 May 11.
Mitochondrial intermembrane space proteins CHCHD2 and CHCHD10 have roles in motor neuron diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy and axonal neuropathy and in Parkinson's disease. They form a complex of unknown function. Here we address the importance of these two proteins in human motor neurons. We show that gene edited human induced pluripotent stem cells (iPSC) lacking either CHCHD2 or CHCHD10 are viable and can be differentiated into functional motor neurons that fire spontaneous and evoked action potentials. Mitochondria in knockout iPSC and motor neurons sustain ultrastructure but show increased proton leakage and respiration, and reciprocal compensatory increases in CHCHD2 or CHCHD10. Knockout motor neurons have largely overlapping transcriptome profiles compared to isogenic control line, in particular for synaptic gene expression. Our results show that the absence of either CHCHD2 or CHCHD10 alters mitochondrial respiration in human motor neurons, inducing similar compensatory responses. Thus, pathogenic mechanisms may involve loss of synaptic function resulting from defective energy metabolism.
线粒体膜间空间蛋白 CHCHD2 和 CHCHD10 在运动神经元疾病（如肌萎缩侧索硬化症、脊髓性肌萎缩症和轴索性神经病）和帕金森病中起作用。它们形成了一个未知功能的复合物。在这里，我们研究了这两种蛋白在人类运动神经元中的重要性。我们发现，缺乏 CHCHD2 或 CHCHD10 的基因编辑人类诱导多能干细胞（iPSC）是有活力的，可以分化为具有自发和诱发动作电位的功能性运动神经元。敲除 iPSC 和运动神经元中的线粒体维持超微结构，但质子泄漏和呼吸增加，CHCHD2 或 CHCHD10 则相应增加。与同基因对照系相比，敲除运动神经元的转录组谱有很大的重叠，特别是在突触基因表达方面。我们的结果表明，CHCHD2 或 CHCHD10 的缺失改变了人类运动神经元中线粒体的呼吸，诱导了类似的补偿反应。因此，致病机制可能涉及由于能量代谢缺陷导致的突触功能丧失。
