Activation of a TFAM‐Dependent Mitochondrial Translational Axis Drives Oxidative Metabolism in Grade 2 Meningiomas

ABSTRACT

Meningiomas exhibit marked biological heterogeneity that is not fully captured by current histopathological grading. Increasing evidence suggests that mitochondrial metabolism contributes to tumor aggressiveness; however, the molecular mechanisms regulating mitochondrial function in meningiomas remain poorly defined. Here, we investigated the role of mitochondrial transcription factor A (TFAM)–driven mitochondrial biogenesis and translation in meningioma progression. We performed integrative transcriptomic, immunohistochemical, and mitochondrial DNA analyses in a well‐characterized cohort of 91 meningiomas, comprising World Health Organization grade 1 (G1) and grade 2 (G2) tumors with long‐term clinical follow‐up. RNA sequencing identified enrichment for mitochondrial metabolic pathways, including oxidative phosphorylation and ATP metabolism, that was preferentially activated in G2 meningiomas. TFAM and its upstream regulator PGC1α were significantly upregulated at both mRNA and protein levels in G2 tumors and exhibited a positive correlation, consistent with enhanced mitochondrial biogenesis. Although mitochondrial DNA copy number did not differ significantly between grades, G2 meningiomas showed a trend toward increased mitochondrial mass. Notably, G2 meningiomas demonstrated marked enrichment of mitoribosomal genes, including MRPL15 , MRPL35 , MRPL42 and MRPS22 , whose expression correlated positively with TFAM and PGC1α expression levels. Network analysis identified TFAM as a central hub linking mitochondrial biogenesis, translation, and metabolic pathway activation. These findings were independently validated using a publicly available meningioma transcriptomic dataset. Together, our results reveal a TFAM‐centered mitochondrial regulatory program that integrates mitochondrial biogenesis, translational capacity, and oxidative metabolism in higher‐grade meningiomas. This mitochondrial translational axis represents a previously unrecognized mechanism underlying meningioma progression and highlights potential metabolic vulnerabilities for therapeutic intervention.