CHCHD2 maintains mitochondrial contact site and cristae organizing system stability and protects against mitochondrial dysfunction in an experimental model of Parkinson's disease.
CHCHD2 maintains mitochondrial contact site and cristae organizing system stability and protects against mitochondrial dysfunction in an experimental model of Parkinson's disease.
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CHCHD2 在帕金森病实验模型中维持线粒体接触位点和嵴组织系统的稳定性并防止线粒体功能障碍
DOI：
10.1097/cm9.0000000000002053
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发表时间：
2022-07-14
影响因子：
6.1
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中科院分区：
文献类型：
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作者：
背景：帕金森病（PD）是继阿尔茨海默氏痴呆之后第二常见的神经退行性疾病。线粒体功能障碍参与 PD 的病理学。含有卷曲螺旋结构域 2 (CHCHD2) 被鉴定与常染色体显性 PD 相关。然而，CHCHD2在PD中的作用机制仍不清楚。方法：采用短发夹RNA（ShRNA）介导的CHCHD2敲低或慢病毒介导的CHCHD2过表达来研究CHCHD2对以人神经母细胞瘤（SHSY5Y）和HeLa细胞为代表的神经元肿瘤细胞系线粒体形态和功能的影响。使用蓝色天然聚丙烯酰胺凝胶电泳（PAGE）和二维十二烷基硫酸钠-PAGE分析来说明CHCHD2在线粒体接触位点和嵴组织系统（MICOS）中的作用。使用免疫共沉淀和免疫印迹来解决 CHCHD2 和 Mic10 之间的相互作用。采用血清型注射腺相关载体介导的CHCHD2和1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)给药来检查CHCHD2在体内的影响。结果：我们发现 CHCHD2 的过表达可以防止甲基-4-苯基吡啶鎓 (MPP+) 诱导的线粒体功能障碍，并抑制 MPTP 诱导的小鼠模型中多巴胺能神经元的损失。此外，我们还发现CHCHD2与Mic10相互作用，CHCHD2的过度表达可以防止MPP+诱导的MICOS损伤，而CHCHD2的敲除会损害MICOS的稳定性。结论：本研究表明CHCHD2可以与Mic10相互作用并维持MICOS复合物的稳定性，有助于保护PD中的线粒体功能。
Background: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's dementia. Mitochondrial dysfunction is involved in the pathology of PD. Coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) was identified as associated with autosomal dominant PD. However, the mechanism of CHCHD2 in PD remains unclear. Methods: Short hairpin RNA (ShRNA)-mediated CHCHD2 knockdown or lentivirus-mediated CHCHD2 overexpression was performed to investigate the impact of CHCHD2 on mitochondrial morphology and function in neuronal tumor cell lines represented with human neuroblastoma (SHSY5Y) and HeLa cells. Blue-native polyacrylamide gel electrophoresis (PAGE) and two-dimensional sodium dodecyl sulfate-PAGE analysis were used to illustrate the role of CHCHD2 in mitochondrial contact site and cristae organizing system (MICOS). Co-immunoprecipitation and immunoblotting were used to address the interaction between CHCHD2 and Mic10. Serotype injection of adeno-associated vector-mediated CHCHD2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration were used to examine the influence of CHCHD2 in vivo. Results: We found that the overexpression of CHCHD2 can protect against methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and inhibit the loss of dopaminergic neurons in the MPTP-induced mouse model. Furthermore, we identified that CHCHD2 interacted with Mic10, and overexpression of CHCHD2 can protect against MPP+-induced MICOS impairment, while knockdown of CHCHD2 impaired the stability of MICOS. Conclusion: This study indicated that CHCHD2 could interact with Mic10 and maintain the stability of the MICOS complex, which contributes to protecting mitochondrial function in PD.