TFAM Loss Induces Oxidative Stress and Divergent Phenotypes in Glioblastoma Metabolic Subtypes

TL;DR

This study shows that TFAM loss affects glioblastoma cells differently depending on their metabolic subtype, influencing growth, stress, and movement.

Contribution

The paper reveals TFAM as a subtype-specific regulator in glioblastoma, with distinct effects on GPM and MTC subtypes.

Findings

TFAM loss in GPM-type cells increases proliferation and ROS production while reducing motility.

TFAM loss in MTC-type cells triggers antioxidant pathways and minimal phenotypic changes.

TFAM overexpression reduces proliferation in GPM-type cells but not in MTC-type cells.

Abstract

Mitochondrial transcription factor A (TFAM) is essential for mitochondrial DNA (mtDNA) maintenance and function, but its role in glioblastoma (GBM) remains largely unexplored. Analysis of patient astrocytomas and TCGA datasets has revealed progressive TFAM downregulation with increasing malignancy, with the lowest expression in glycolytic/plurimetabolic (GPM) subtypes. Functional and transcriptomic profiling of mesenchymal GBM cell lines showed that TFAM silencing in GPM-type U87MG cells enhanced proliferation, S-phase entry, reactive oxygen species (ROS) production, and adhesion, while reducing motility. These changes were correlated with upregulation of LDHC and TRAF2 and downregulation of androgen receptor-linked motility genes and LOXL2. By contrast, TFAM loss in mitochondrial (MTC)-type A172 cells caused minimal phenotypic alterations, associated with elevated SOD1 expression and activation of antioxidant, mitochondrial membrane, and survival pathways, alongside suppression of oxidative phosphorylation and vesicle-trafficking genes. TFAM overexpression reduced proliferation in U87MG but had a limited impact on A172 cells. Taken together, these findings establish TFAM as a subtype-specific regulator of GBM cell proliferation, redox balance, and motility. TFAM loss drives a proliferative, ROS-sensitive phenotype in GPM-type cells, while eliciting adaptive, stress-resilient programs in MTC-type cells. This study identifies TFAM and downstream effectors, TRAF2 and LOXL2, as potential therapeutic targets, supporting the development of metabolic subtype-tailored strategies for GBM treatment.

Figures