基于MitCOM的预后模型通过调节线粒体结构和代谢，将GLUD1鉴定为胶质母细胞瘤生长和侵袭的关键抑制因子。

MitCOM-based prognostic model identifies GLUD1 as a key suppressor of glioblastoma growth and invasion through regulation of mitochondrial structure and metabolism.

作者信息

Li Yang, Qin Chaoying, Jiang Liangqi, Su Jun, Li Zhen, Liu Qing, Yao Yuanbing

机构信息

Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China.

Clinical Research Center for Skull Base Surgery and Neurooncology in Hunan Province, 87 Xiangya Road, Changsha, Hunan, 410008, China.

出版信息

Cancer Cell Int. 2025 Jun 21;25(1):222. doi: 10.1186/s12935-025-03875-y.

DOI:10.1186/s12935-025-03875-y

PMID:40544265

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12182657/

Abstract

BACKGROUND

Glioblastoma (GBM) is a highly aggressive brain tumour with a poor prognosis. Mitochondrial dysfunction, including changes in oxidative phosphorylation, reactive oxygen species (ROS) production, and cristae organisation, plays a key role in the progression of GBM. However, the role of mitochondrial protein complexes in GBM biology is poorly understood.

METHODS

Bioinformatics analyses of GBM datasets and mitochondrial complexome profiling (‘MitCOM’) identified mitochondrial protein complex genes (MitCOMGs) with prognostic significance. A six-gene prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression and validated in independent cohorts. GLUD1, the most significant gene, was further validated through in vitro assays, including Blue Native PAGE, metabolomic profiling, and various cell assays.

RESULTS

GLUD1 expression was downregulated in GBM and associated with poor survival. Functional studies showed that GLUD1 regulates mitochondrial crista organisation and metabolic reprogramming. GLUD1 overexpression disrupted mitochondrial integrity, impaired respiratory chain complex assembly, and reduced adenosine triphosphate production. Metabolomic profiling revealed altered amino acid metabolism and tricarboxylic acid cycle intermediates that inhibited GBM cell proliferation and invasion.

CONCLUSIONS

GLUD1 is a key mitochondrial regulator in GBM, and its downregulation contributes to tumour progression through mitochondrial dysfunction and metabolic reprogramming. The six-gene MitCOMG model offers robust prognostic value and identified GLUD1 as a potential therapeutic target for GBM.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1186/s12935-025-03875-y.

摘要

背景

胶质母细胞瘤（GBM）是一种侵袭性很强的脑肿瘤，预后较差。线粒体功能障碍，包括氧化磷酸化、活性氧（ROS）产生和嵴组织的变化，在GBM的进展中起关键作用。然而，线粒体蛋白复合物在GBM生物学中的作用尚不清楚。

方法

对GBM数据集进行生物信息学分析和线粒体复合物组分析（“MitCOM”），确定具有预后意义的线粒体蛋白复合物基因（MitCOMGs）。使用最小绝对收缩和选择算子（LASSO）回归构建了一个六基因预后模型，并在独立队列中进行了验证。通过体外试验，包括蓝色天然聚丙烯酰胺凝胶电泳、代谢组学分析和各种细胞试验，对最显著的基因GLUD1进行了进一步验证。