Mitochondrial electron transport chain gene-based prognostic model identifies SDHB as a key regulator of low-grade glioma progression and therapeutic target.

Abstract

Background: Low-grade gliomas (LGG) are a heterogeneous category of brain tumors characterized by a variable clinical course, frequently associated with unfavorable prognosis and therapeutic challenges. Understanding the molecular mechanisms underlying LGG progression is crucial for improving prognosis and therapeutic strategies. This study integrates single-cell RNA sequencing and bioinformatics to explore the role of METCGs (mitochondrial electron transport chain genes) in LGG and construct a predictive model for prognosis, and through in vitro experiments, the feasibility of this model was validated.

Methods: We analyzed 5,691 cells and 22,947 genes from the GSE117891 dataset. Using cell marker genes from the CellMarker 2.0 database and classical markers, we identified four distinct cell types: oligodendrocytes, T cells, astrocytes, and microglial cells. The METCGs profiles were calculated using various algorithms, including AUCell, UCell, ssGSEA, and others. Differentially expressed genes (DEGs) were identified and enriched for relevant pathways. Machine learning algorithms were employed to construct a prognostic risk model based on five selected METCGs. The model was validated using independent LGG cohorts. Biological pathway analyses, immune infiltration profiles, and potential drug targets were also explored. To validate the reliability of this model through experiments, functional experiments, including Blue native Page (BN-Page), western blotting, immunofluorescence, and cell viability assays, were conducted to validate SDHB expression and its role in LGG progression.

Results: Astrocytes exhibited the highest METCG scores, indicating their central role in mitochondrial energy regulation. The prognostic model, constructed using the StepCox[forward] + plsRcox approach, included five genes: SDHB, SDHC, SLC25A27, UQCRB, and NDUFA13. The model demonstrated high prognostic accuracy with an average C-index of 0.67 and successfully stratified LGG patients into low- and high-risk groups. High-risk patients had worse survival outcomes, with significant differences observed in KEGG pathways, immune infiltration, and metabolic processes. The low-risk group exhibited higher immune cell infiltration, including follicular helper T and monocyte cells. AZD1208_1449 was identified as a potential drug targeting high-risk patients. Additionally, SDHB expression was significantly higher in LGG cells, and knockdown of SDHB inhibited cell proliferation and invasion, supporting its role in tumor progression.

Conclusion: This study provides a comprehensive analysis of METCGs in LGG and develops a robust prognostic model for patient stratification. SDHB, a key subunit of Complex II, plays a crucial role in mitochondrial function and tumor progression. Our findings suggest that he high expression of SDHB in LGG contributes to maintaining elevated SDH and Complex II activity, ensuring the structural and functional integrity of mitochondrial ETC complexes. This supports the high ROS production and MMP required for the rapid growth of LGG, thereby promoting its proliferation and invasion. Thus, targeting SDHB and its associated pathways could offer new therapeutic avenues for LGG treatment.