中国医学科学院张晓蓉研究小组的揭示了线粒体呼吸复合体IV缺乏是肌萎缩性侧索硬化症的表现。该研究于2025年3月11日发表于《自然—神经科学》杂志上。

为了确定这一缺陷在ALS中的介导作用，研究小组利用基于转录激活因子样效应的线粒体基因组编辑技术，在大鼠神经元中引入CIV亚基突变。他们的研究结果表明，神经元CIV缺陷足以介导许多ALS样表型，包括胞质TAR DNA结合蛋白43重分布、选择性运动神经元丢失和瘫痪。这些结果强调了CIV缺陷是sALS的潜在主题，并揭示了运动神经元的特异性易感性，标志着对sALS的理解和治疗发展的重要进展。

研究人员表示，肌萎缩性侧索硬化症（ALS）分为~10%的家族性和~90%的散发性病例。虽然家族性ALS是由许多不同功能基因的突变引起的，但ALS的潜在致病机制，特别是散发性ALS (sALS)，在很大程度上是未知的。值得注意的是，大约一半的sALS患者出现线粒体呼吸复合体IV （CIV）缺陷。

附：英文原文

Title: Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis

Author: Cheng, Man, Lu, Dan, Li, Kexin, Wang, Yan, Tong, Xiwen, Qi, Xiaolong, Yan, Chuanzhu, Ji, Kunqian, Wang, Junlin, Wang, Wei, Lv, Huijiao, Zhang, Xu, Kong, Weining, Zhang, Jian, Ma, Jiaxin, Li, Keru, Wang, Yaheng, Feng, Jingyu, Wei, Panpan, Li, Qiushuang, Shen, Chengyong, Fu, Xiang-Dong, Ma, Yuanwu, Zhang, Xiaorong

Issue&Volume: 2025-03-11

Abstract: Amyotrophic lateral sclerosis (ALS) is categorized into ~10% familial and ~90% sporadic cases. While familial ALS is caused by mutations in many genes of diverse functions, the underlying pathogenic mechanisms of ALS, especially in sporadic ALS (sALS), are largely unknown. Notably, about half of the cases with sALS showed defects in mitochondrial respiratory complex IV (CIV). To determine the causal role of this defect in ALS, we used transcription activator-like effector-based mitochondrial genome editing to introduce mutations in CIV subunits in rat neurons. Our results demonstrate that neuronal CIV deficiency is sufficient to cause a number of ALS-like phenotypes, including cytosolic TAR DNA-binding protein 43 redistribution, selective motor neuron loss and paralysis. These results highlight CIV deficiency as a potential cause of sALS and shed light on the specific vulnerability of motor neurons, marking an important advance in understanding and therapeutic development of sALS.

DOI: 10.1038/s41593-025-01896-4

Source: https://www.nature.com/articles/s41593-025-01896-4