TSPO-Mediated Mitochondrial Coupling with the Nucleus Drives Cholesterol Metabolism and Chemoresistance in Glioblastoma

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Glioblastoma (GBM) is the most aggressive and lethal primary brain tumour in adults. Beyond genetic and signaling abnormalities, metabolic reprogramming plays a pivotal role in GBM progression. Among these alterations, cholesterol metabolism has emerged as a distinctive hallmark of glioblastoma biology, drawing attention to pathways that regulate lipid homeostasis. Here, through integrated in vitro and in vivo approaches, we demonstrate that the 18 kDa cholesterol-binding mitochondrial protein TSPO is essential for the tumorigenic potential of GBM and is closely associated with enhanced cholesterol metabolism. We further identify TSPO as a key factor required for the formation of Nucleus-Associated Mitochondria (NAM)—newly characterized contact sites that glioblastoma cells exploit to evade cell death induced by the chemotherapeutic agent temozolomide (TMZ). Through NAMs, TMZ promotes the expression of the nuclear transcription factor SREBP1 and stabilizes the oncogenic coactivators YAP and TAZ, fostering a pro-survival transcriptional program. Disruption of NAM via TSPO targeting counteracts these effects andrestores chemosensitivity to TMZ. Collectively, our findings reveal that the physical and functional coupling between mitochondria and the nucleus constitutes a metabolic and signaling hub of chemoresistance in glioblastoma. Targeting TSPO emerges as a promising strategy to dismantle this relay and enhance therapeutic efficacy

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