統合トランスクリプトーム解析により、グリオブラストーマにおけるMTHFD2関連のミトコンドリア機能不全とマクロファージの不均一性が明らかになる
Binfeng Tu1, Yulong Ji2, Zilong Tan1
1The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, P R China.
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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