Integrated transcriptomic analysis reveals mitochondrial dysregulation and macrophage heterogeneity associated with MTHFD2 in glioblastoma

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2026-03-01 Epub Date: 2026-01-31 DOI:10.1016/j.brainresbull.2026.111758

Binfeng Tu , Yulong Ji , Zilong Tan , Shiqi Cheng , Yan Zhang

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引用次数: 0

Abstract

Background

Glioblastoma (GBM) is an aggressive brain tumor with therapeutic resistance and poor prognosis. Mitochondrial dysfunction has emerged as a critical driver of tumor progression and immune modulation, yet mitochondrial gene alterations and their cellular specificity in GBM remain unclear.

Methods

Transcriptomic datasets (TCGA-GBM, GSE66354) were analyzed to identify differentially expressed mitochondria-associated genes using MitoCarta3.0. Prognostic mitochondrial DEGs (MitoDEGs) were determined by Cox regression, and a nomogram was constructed for survival prediction. Single-cell RNA sequencing was applied to explore mitochondrial gene expression in cellular populations, particularly macrophages. Functional enrichment and pseudotime analyses were conducted to define macrophage subpopulations, while in vitro assays validated the role of MTHFD2 in glioblastoma cell behavior, macrophage migration and the expression of IL-6 and CCL2.

Results

MTHFD2 was identified as a diagnosis mitochondrial hub gene strongly correlated with GBM diagnosis. Single-cell analysis revealed elevated mitochondrial activity and MTHFD2 expression in tumor-associated macrophages. A distinct MTHFD2-high macrophage subpopulation displayed immune-activated and metabolically reprogrammed pathways, representing a terminally differentiated state linked to tumor progression. Functional assays showed that silencing MTHFD2 suppressed glioblastoma cell proliferation, invasion, colony formation, and reduced macrophage migration and the expression of IL-6 and CCL2.

Conclusion

Mitochondrial dysfunction mediated by MTHFD2 in macrophages plays a key role in GBM progression and immune heterogeneity. MTHFD2 represents a potential diagnostic biomarker and therapeutic target for modulating GBM immune infiltration.

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综合转录组学分析揭示了胶质母细胞瘤中与MTHFD2相关的线粒体失调和巨噬细胞异质性。

背景：胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，治疗耐药，预后差。线粒体功能障碍已成为肿瘤进展和免疫调节的关键驱动因素，但线粒体基因改变及其在GBM中的细胞特异性尚不清楚。方法：利用MitoCarta3.0分析转录组学数据集（TCGA-GBM, GSE66354），鉴定线粒体相关基因的差异表达。采用Cox回归法测定预后线粒体deg (mitodeg)，并构建生存预测nomogram。单细胞RNA测序应用于探索线粒体基因在细胞群体中的表达，特别是巨噬细胞。通过功能富集和伪时间分析来定义巨噬细胞亚群，而体外实验验证了MTHFD2在胶质母细胞瘤细胞行为、巨噬细胞迁移以及IL-6和CCL2表达中的作用。结果：MTHFD2是与GBM诊断密切相关的诊断线粒体中枢基因。单细胞分析显示，肿瘤相关巨噬细胞线粒体活性和MTHFD2表达升高。不同的mthfd2高巨噬细胞亚群显示免疫激活和代谢重编程途径，代表与肿瘤进展相关的最终分化状态。功能分析显示，沉默MTHFD2抑制胶质母细胞瘤细胞的增殖、侵袭、集落形成，减少巨噬细胞迁移和IL-6和CCL2的表达。结论：巨噬细胞MTHFD2介导的线粒体功能障碍在GBM的进展和免疫异质性中起关键作用。MTHFD2是调节GBM免疫浸润的潜在诊断生物标志物和治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.