Department of Neurosurgery, Xiangya Hospital, Central South University, No. 87 Xiangya Rd., Changsha, 410008, Hunan, People's Republic of China.
Hypothalamic-Pituitary Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Apoptosis. 2023 Oct;28(9-10):1452-1468. doi: 10.1007/s10495-023-01865-x. Epub 2023 Jul 6.
Mitochondrial dysfunction and necroptosis are closely associated, and play vital roles in the medical strategy of multiple cardiovascular diseases. However, their implications in intracranial aneurysms (IAs) remain unclear. In this study, we aimed to explore whether mitochondrial dysfunction and necroptosis could be identified as valuable starting points for predictive, preventive, and personalized medicine for IAs. The transcriptional profiles of 75 IAs and 37 control samples were collected from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs), weighted gene co-expression network analysis, and least absolute shrinkage and selection operator (LASSO) regression were used to screen key genes. The ssGSEA algorithm was performed to establish phenotype scores. The correlation between mitochondrial dysfunction and necroptosis was evaluated using functional enrichment crossover, phenotype score correlation, immune infiltration, and interaction network construction. The IA diagnostic values of key genes were identified using machine learning. Finally, we performed the single-cell sequencing (scRNA-seq) analysis to explore mitochondrial dysfunction and necroptosis at the cellular level. In total, 42 IA-mitochondrial DEGs and 15 IA-necroptosis DEGs were identified. Screening revealed seven key genes invovled in mitochondrial dysfunction (KMO, HADH, BAX, AADAT, SDSL, PYCR1, and MAOA) and five genes involved in necroptosis (IL1B, CAMK2G, STAT1, NLRP3, and BAX). Machine learning confirmed the high diagnostic value of these key genes for IA. The IA samples showed higher expression of mitochondrial dysfunction and necroptosis. Mitochondrial dysfunction and necroptosis exhibited a close association. Furthermore, scRNA-seq indicated that mitochondrial dysfunction and necroptosis were preferentially up-regulated in monocytes/macrophages and vascular smooth muscle cells (VSMCs) within IA lesions. In conclusion, mitochondria-induced necroptosis was involved in IA formation, and was mainly up-regulated in monocytes/macrophages and VSMCs within IA lesions. Mitochondria-induced necroptosis may be a novel potential target for diagnosis, prevention, and treatment of IA.
线粒体功能障碍和坏死性凋亡密切相关，在多种心血管疾病的医学策略中起着至关重要的作用。然而，它们在颅内动脉瘤（IA）中的意义尚不清楚。在这项研究中，我们旨在探讨线粒体功能障碍和坏死性凋亡是否可以作为预测、预防和个体化治疗 IA 的有价值的起点。从基因表达综合数据库（GEO）中收集了 75 个 IA 和 37 个对照样本的转录谱。使用差异表达基因（DEG）、加权基因共表达网络分析和最小绝对收缩和选择算子（LASSO）回归筛选关键基因。使用 ssGSEA 算法建立表型评分。使用功能富集交叉、表型评分相关性、免疫浸润和相互作用网络构建评估线粒体功能障碍和坏死性凋亡之间的相关性。使用机器学习识别关键基因的 IA 诊断价值。最后，我们进行了单细胞测序（scRNA-seq）分析，以探索细胞水平的线粒体功能障碍和坏死性凋亡。总共鉴定出 42 个与 IA 相关的线粒体 DEG 和 15 个与 IA 相关的坏死性凋亡 DEG。筛选出 7 个涉及线粒体功能障碍的关键基因（KMO、HADH、BAX、AADAT、SDSL、PYCR1 和 MAOA）和 5 个涉及坏死性凋亡的基因（IL1B、CAMK2G、STAT1、NLRP3 和 BAX）。机器学习证实了这些关键基因对 IA 具有较高的诊断价值。IA 样本表现出更高的线粒体功能障碍和坏死性凋亡表达。线粒体功能障碍和坏死性凋亡之间存在密切关联。此外，scRNA-seq 表明，IA 病变中的单核细胞/巨噬细胞和血管平滑肌细胞（VSMCs）中优先上调线粒体功能障碍和坏死性凋亡。总之，线粒体诱导的坏死性凋亡参与了 IA 的形成，主要在上皮细胞和 VSMCs 中上调。线粒体诱导的坏死性凋亡可能是 IA 诊断、预防和治疗的新的潜在靶点。
