NEU1 sustains mitochondria-lysosome contacts to trigger lysosomal Cu2+/cathepsin escape and mitochondrial lysis in glioblastoma (NeuLysis)

BACKGROUND: Mitochondria-lysosome contacts regulates metabolic reprogramming in cancer, yet its role in glioblastoma pathogenesis remains poorly defined. METHODS: We employed an integrated approach, including transmission electron microscopy (TEM) and Hessian-structured illumination microscopy (Hessian SIM), Fluorescence Resonance Energy Transfer-Fluorescence Lifetime Imaging (FRET-FLIM) assays, targeted metabolomics, mitochondrial respiration analyses, subcellular fractionation, and in vivo orthotopic xenograft models. RESULTS: Genetic depletion or pharmacological disruption using EPIC-1042 against PTRF led to NEU1 destabilization via lysosome-dependent degradation, potentiating lysosomal function and prolonging mitochondria-lysosome contacts duration. Within this sustained contact state, dual flux transported from lysosomes to mitochondria: (1) Cu²⁺, which triggered DLAT aggregation and induced cuproptosis; and (2) cathepsin B, which caused mitochondrial protein degradation. Consequently, morphology and function were destroyed. NEU1 deficiency phenocopied these effects and heightened sensitivity to copper ionophore Elesclomol. Pharmacological inhibition of NEU1 with Oseltamivir synergized potently with Elesclomol to suppress intracranial glioblastoma overall growth and significantly extend survival in vivo. CONCLUSIONS: We depict NeuLysis (NEU1-induced Lysosomal Escape leading to mitochondrial Lysis) as a novel cell death pathway in glioblastoma, wherein PTRF-NEU1 axis prolonged mitochondria-lysosome contacts. Pharmacological NEU1 inhibition with Oseltamivir synergizes Elesclomol-induced cell death, providing a preclinically actionable therapeutic strategy against glioblastoma.