基于生物信息学分析和体外实验确定电压依赖性阴离子通道1作为杜氏肌营养不良症的线粒体相关靶点

Identification of VDAC1 as a mitochondria-related target of Duchenne muscular dystrophy based on bioinformatics analysis and in vitro experiments.

作者信息

Wu Wenjuan, Song Xueqin, Li Baoguang

机构信息

Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; Department of Neurology, Hebei Children's Hospital, The Key Laboratory of Pediatric Epilepsy and Neurology of Hebei Province, Shijiazhuang 050031, China.

Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; The Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang 050000, China; Neurological Laboratory of Hebei Province, Shijiazhuang 050000, China.

出版信息

Int Immunopharmacol. 2025 Jun 17;158:114836. doi: 10.1016/j.intimp.2025.114836. Epub 2025 May 12.

DOI:10.1016/j.intimp.2025.114836

PMID:40359883

Abstract

BACKGROUND

Mitochondrial dysfunction is a well-recognized pathological feature of Duchenne Muscular Dystrophy (DMD). The potential regulatory role of mitochondria-related genes (MRGs) in DMD remains to be further explored.

METHODS

GEO datasets and MRGs were used to analysis mitochondrial scores and evaluate patients' immunological characteristics. Weighted gene co-expression network analysis, differentially expressed genes (DEGs) and MRGs were used to identify hub genes. A specific hub gene was selected, and the effects of this gene overexpression on a horse serum (HS) treated C2C12 cell in vitro model were investigated.

RESULTS

Mitochondrial score was decreased in DMD group. Significant differences were observed in 12 immune cell types in normal/DMD and high/low mitochondrial score groups. 9 hub genes were identified, with 7 validated. Among them, VDAC1 was selected for further study. Overexpression of VDAC1 in HS C2C12 myoblasts promoted cell proliferation, reduced apoptosis rate and the Bax expression (with concurrent Bcl2 upregulation), diminished LDH release to reduce cytotoxicity, decreased intracellular ROS levels to alleviate oxidative stress, inhibited the expression of autophagy (LC3) and atrophy (Atrogin-1 and MuRF-1) markers, and promoted differentiation.

CONCLUSION

In conclusion, VDAC1 may participate in the myoblast proliferation and myotube atrophy by influencing mitochondrial function, which may serve as a new target for DMD treatment.

摘要

背景

线粒体功能障碍是杜氏肌营养不良症（DMD）公认的病理特征。线粒体相关基因（MRGs）在DMD中的潜在调节作用仍有待进一步探索。

方法

利用基因表达综合数据库（GEO）数据集和MRGs分析线粒体评分并评估患者的免疫特征。采用加权基因共表达网络分析、差异表达基因（DEGs）和MRGs来识别枢纽基因。选择一个特定的枢纽基因，研究该基因过表达对马血清（HS）处理的C2C12细胞体外模型的影响。

结果

DMD组线粒体评分降低。在正常/DMD组和高/低线粒体评分组的12种免疫细胞类型中观察到显著差异。鉴定出9个枢纽基因，其中7个得到验证。其中，选择电压依赖性阴离子通道1（VDAC1）进行进一步研究。VDAC1在HS C2C12成肌细胞中的过表达促进细胞增殖，降低凋亡率和Bax表达（同时上调Bcl2），减少乳酸脱氢酶（LDH）释放以降低细胞毒性，降低细胞内活性氧（ROS）水平以减轻氧化应激，抑制自噬（LC3）和萎缩（Atrogin-1和MuRF-1）标志物的表达，并促进分化。