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Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy
Brain Pathology ( IF 5.8 ) Pub Date : 2023-03-28 , DOI: 10.1111/bpa.13157
Tingting Dong 1, 2 , Zai-Qiang Zhang 3 , Li-Hong Sun 4 , Weilong Zhang 5 , Zhaohui Zhu 6 , Lin Lin 1 , Lin Yang 1 , An Lv 4 , Chunying Liu 4 , Qing Li 1 , Rui-Feng Yang 7 , Xiuru Zhang 8 , Yamei Niu 1, 9 , Hou-Zao Chen 7 , De-Pei Liu 7 , Wei-Min Tong 1, 9
Affiliation  

Mitochondrial encephalomyopathies (ME) are frequently associated with mutations of mitochondrial DNA, but the pathogenesis of a subset of ME (sME) remains elusive. Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities with insulted mitochondrial structure and neuronal loss in mice. In addition, haploinsufficiency of Mic60 reduces mitochondrial membrane potential and cellular ATP production, increases reactive oxygen species, and alters mitochondrial oxidative phosphorylation complexes in neurons in an age-dependent manner. Moreover, haploinsufficiency of Mic60 compromises brain glucose intake and oxygen consumption in mice, resembling human ME syndrome. We further discover that MIC60 protein expression declined significantly in human sME, implying that insufficient MIC60 may contribute for pathogenesis of human ME. Notably, systemic administration of antioxidant N-acetylcysteine largely reverses mitochondrial dysfunctions and metabolic disorders in haplo-insufficient Mic60 mice, also restores neurological abnormal symptom. These results reveal Mic60 is required in the maintenance of mitochondrial integrity and function, and likely a potential therapeutics target for mitochondrial encephalomyopathies.

中文翻译:

Mic60 对于维持线粒体完整性和预防脑肌病至关重要

线粒体脑肌病 (ME) 经常与线粒体 DNA 突变相关,但 ME (sME) 亚型的发病机制仍然难以捉摸。在此,我们报告线粒体内膜蛋白 Mic60 的单倍体不足会导致小鼠进行性神经系统异常,线粒体结构受损和神经元丢失。此外,Mic60的单倍体不足会降低线粒体膜电位和细胞 ATP 的产生,增加活性氧,并以年龄依赖性方式改变神经元中的线粒体氧化磷酸化复合物。此外,Mic60的单倍体不足会损害小鼠的大脑葡萄糖摄入和耗氧量,类似于人类 ME 综合征。我们进一步发现,人类 sME 中 MIC60 蛋白表达显着下降,这意味着 MIC60 不足可能导致人类 ME 的发病。值得注意的是,全身给予抗氧化剂N-乙酰半胱氨酸在很大程度上逆转了单倍体不足的Mic60小鼠的线粒体功能障碍和代谢紊乱,也恢复了神经系统异常症状。这些结果表明 Mic60 是维持线粒体完整性和功能所必需的,并且可能是线粒体脑肌病的潜在治疗靶点。
更新日期:2023-03-28
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