Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells.

UNLABELLED: Glioblastoma stem cells (GSC) exhibit remarkable metabolic and epigenetic adaptability, contributing to therapeutic resistance and tumor recurrence. The mechanisms underlying this plasticity represent potential targetable vulnerabilities to improve glioblastoma treatment. In this study, we identified a critical metabolic-epigenetic axis centered on the mitochondrial calcium uniporter (MCU) that governs GSC survival and tumor initiation. MCU was preferentially expressed in GSCs, and loss of MCU significantly impaired GSC self-renewal and viability. Mechanistically, MCU enhanced mitochondrial calcium uptake, promoting acetyl-CoA production via pyruvate dehydrogenase activation. Elevated acetyl-CoA levels drove histone H3K27 acetylation at the tribbles homolog 3 locus to maintain GSC growth. In patients with glioblastoma, higher MCU expression was correlated with increased acetyl-CoA levels, elevated H3K27 acetylation, enhanced tribbles homolog 3 expression, higher tumor grade, and poorer survival. Pharmacologic inhibition of MCU with berberine suppressed GSC growth and extended survival in mouse glioblastoma multiforme models. These findings establish MCU as a critical link between mitochondrial metabolism and epigenetic regulation, highlighting its potential as a therapeutic target for glioblastoma.

SIGNIFICANCE: A metabolic-epigenetic axis involving MCU and H3K27 acetylation enhances glioblastoma stem cell self-renewal and proliferation to promote tumor initiation and can be targeted as a therapeutic intervention for glioblastoma.