LRRC4 Orchestrates AP2A1‐Containing Clathrin‐Coated Vesicles to Disrupt Mitochondrial Cristae and Restrict Glioblastoma Progression

ABSTRACT Mitochondrial dynamics and metabolic homeostasis are pivotal for the aggressive progression of glioblastoma (GBM); however, how membrane‐bound organelles modulate mitochondrial remodeling remains unclear. In this study, we identified LRRC4 as a Golgi‐anchored tumor suppressor that coordinates a novel vesicle‐to‐mitochondrial axis to inhibit tumor growth. Using single‐sample gene set enrichment analysis (ssGSEA), w e established a mitoDynamic score and identified LRRC4 as a key downregulated regulator associated with poor prognosis. Mechanistic analyses combining transmission electron microscopy, Blue Native PAGE, showed that LRRC4 engages AP2A1‐containing clathrin‐coated vesicles in the Golgi apparatus and redirects them to the inner mitochondrial membrane. This targeted vesicular recruitment disrupted the MICOS complex, suppressing Mic60 expression, resulting in cristae collapse, respiratory chain destabilization, and impaired oxidative phosphorylation. Functional assays and xenograft models have demonstrated that structural and metabolic remodeling triggers excessive mitophagy, depletes cellular metabolic fitness, and suppresses GBM proliferation and invasion. Integrating mitoDynamic scoring with mechanistic and rescue experiments established the LRRC4–AP2A1–Mic60 axis as a validated mitochondrial vulnerability. Collectively, these findings revealed a previously unrecognized Golgi mitochondria crosstalk, demonstrated that clathrin‐coated vesicles can act as active modulators of mitochondrial architecture, and suggested that targeting Golgi‐derived clathrin‐coated vesicle‐mediated mitochondrial remodeling is a novel therapeutic strategy for GBM.