Mitochondrial Supercomplex‐Associated Proximity Increases in Malignant Glioma Tissue

In rapidly growing tumors, including gliomas, heterogeneous microenvironments with fluctuating oxygen and nutrient availability impose strong selective pressure for metabolic adaptation. For over a century, mitochondria have been recognized as central to the reprogramming of cancer metabolism. However, it remains unclear whether and how remodeling of oxidative phosphorylation (OXPHOS), including organization of electron transport chain (ETC) complexes, contributes to the proliferation of cancer cells. Recent reports suggest that mitochondrial supercomplexes (SCs), higher-order assemblies of ETC complexes, are enriched in tumor cells and may support proliferation by increasing respiratory efficiency and stabilizing electron transfer. Here, we evaluated respiratory SC formation across glioma grades by quantifying ETC complex proximity within mitochondria in patient tissue using proximity ligation assay (PLA). We observed increased PLA signal between ETC complexes I and IV, consistent with increased respirasome assembly, that was associated with malignant glioma (Grades III and IV), and increased proximity between ETC Complexes III and IV that was most prominent in proliferating glioblastoma (Grade IV) cells. Although the precise functions of SCs remain debated, these increases in high-grade glioma relative to Grade II and control tissue suggest that SC remodeling may be a feature of malignant glioma metabolic remodeling.