Mitochondrial biogenesis fuels the energetic demands of grade 2 meningiomas

Meningioma is the most common primary intracranial tumor, accounting for 37.6% of all brain tumors, and is predominantly classified as grade 1 (G1) or 2 (G2). While G1 tumors typically follow a benign clinical course, G2 meningiomas are more aggressive and exhibit higher recurrence rates. Despite their clinical relevance, the metabolic features of G2 meningiomas - particularly the contribution of mitochondrial function - remain poorly defined. Mitochondria, the cellular powerhouses responsible for ATP production, are essential for meeting the elevated metabolic demands of tumor growth. Prior transcriptomic studies suggest that G2 meningiomas exhibit enhanced oxidative metabolism, cell division, and motility. The objective of this study was to identify mitochondrial components that support the bioenergetic requirements of G2 tumors. Transcriptomic analysis revealed elevated expression of TFAM, the master regulator and protector of mitochondrial DNA (mtDNA), in G2 compared to G1 meningiomas. Its transcriptional coactivator PGC1-alpha (encoded by PPARGC1A ) was also upregulated, and both genes demonstrated a strong positive correlation, suggesting that the TFAM/PGC1-alpha axis may drive increased mtDNA copy number in G2 tumors. Immunostaining confirmed grade-specific TFAM localization, with G2 tumors displaying more diffuse cytosolic distribution. Furthermore, G2 meningiomas showed increased mitochondrial activity, evidenced by upregulated mitoribosomal gene expression and activation of oxidative phosphorylation and tricarboxylic acid cycle pathways. Collectively, these findings indicate that the TFAM/PGC1-alpha/mtDNA axis is activated in G2 meningiomas, potentially enabling the elevated energy production needed to sustain their increased proliferative and migratory capacity.