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

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 <i>TFAM</i> 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 <i>LDHC</i> and <i>TRAF2</i> and downregulation of androgen receptor-linked motility genes and <i>LOXL2</i>. By contrast, TFAM loss in mitochondrial (MTC)-type A172 cells caused minimal phenotypic alterations, associated with elevated <i>SOD1</i> 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, <i>TRAF2</i> and <i>LOXL2</i>, as potential therapeutic targets, supporting the development of metabolic subtype-tailored strategies for GBM treatment.