Targeting the Mitochondria in High-Grade Gliomas

High-grade gliomas are aggressive primary brain tumors and often fatal. They are characterized by rapid growth, treatment resistance, and significant heterogeneity both within and between tumors. A growing body of evidence highlights the mitochondria, dynamic organelles essential for energy production, apoptosis regulation, and metabolic rewiring, as a critical driver in glioma progression and treatment resistance. As a result, these insights have sparked growing interest in mitochondrial-directed therapies. This review highlights the distinct metabolic features and mitochondrial processes of glioma, outlining the rationale for targeting mitochondrial function. We discuss recent advances in mitochondrial-targeted therapies, with a focus on caseinolytic protease P (ClpP) agonism as a breakthrough in the treatment of diffuse midline glioma (DMG). Moreover, we discuss the pathogenic link between mitochondrial metabolism and epigenetic regulation, and the potential therapeutic benefit of disrupting this interaction.