Mitochondrial Metabolic Reprogramming in Glioma: Mechanisms of Tumorigenesis and Implications for Clinical Therapy

ABSTRACT Background Gliomas are metabolically heterogeneous tumors in which mitochondria coordinate bioenergetics, biosynthesis, redox homeostasis, stress adaptation, and treatment responses. This review examines mitochondrial dependencies across glioma subtypes and cell states. Methods We synthesized evidence on mitochondrial integration of glucose, amino acid and protein, lipid, and nucleotide metabolism, together with mitochondrial genetics, signaling, intercellular transfer, and barriers to therapeutic translation in gliomas. Results Glioma glucose metabolism does not follow a uniform Warburg phenotype. IDH‐mutant gliomas exhibit D‐2‐hydroxyglutarate‐driven metabolic and epigenetic remodeling, whereas IDH‐wild‐type glioblastomas contain glycolytic, oxidative phosphorylation‐enriched, and adaptable stem‐like states. Mitochondrial proteostasis links protein import and translation with PI3K/AKT/mTOR signaling, the ubiquitin–proteasome system, autophagy, and mitophagy. Lipid synthesis, storage, fatty acid oxidation, and cardiolipin homeostasis support metabolic adaptation. Electron transport, aspartate availability, redox balance, and dihydroorotate dehydrogenase connect mitochondria with nucleotide synthesis, DNA repair, and treatment resistance. Mitochondrial DNA alterations, mitonuclear signaling, and intercellular mitochondrial transfer further influence respiratory adaptation and tumorigenicity. Metabolic compensation and intratumoral heterogeneity limit single‐target therapies, whereas clinical evidence supports genotype‐directed intervention, exemplified by vorasidenib. Conclusions Effective mitochondrial targeting requires biomarkers that match metabolic dependencies to molecular subtypes and cell states while accounting for brain exposure, compensation, and toxicity.