A Coordinated Mitochondrial Genome Expression Program Marks a Differentiated Neural-Lineage and Synaptic Transcriptional State in Lower-Grade Glioma

Mitochondria regulate cellular metabolism, signaling, and cell fate, yet the biological significance of coordinated mitochondrial genome transcription in lower-grade glioma (LGG) remains unclear. We integrated transcriptomic and clinical data from the TCGA and CGGA cohorts to investigate expression of the 13 mitochondrial DNA-encoded protein-coding genes (mtPCGs). Elevated expression of all mtPCGs was consistently associated with favorable molecular subtypes and prolonged overall survival (OS). Transcriptome-wide correlation and Gene Ontology analyses revealed a coordinated program enriched for synaptic signaling, neurotransmission, postsynaptic organization, and neuronal differentiation, accompanied by positive correlations with neuronal and synaptic markers and negative correlations with stemness and immune-associated markers. Although the mitochondrial transcriptional score was not independently associated with survival after adjustment for established clinicomolecular variables, it consistently marked biologically less aggressive tumors. Coordinated mitochondrial genome expression identifies a neuron-like transcriptional state associated with favorable LGG biology, revealing an unexpected link between mitochondrial transcription, synaptic identity, and glioma differentiation.