PGC1a Degradation Suppresses Mitochondrial Biogenesis to Confer Radiation Resistance in Glioma

Radiotherapy is a major component of standard-of-care treat-ment for gliomas, the most prevalent type of brain tumor. However, resistance to radiotherapy remains a major concern. Identification of mechanisms governing radioresistance in gliomas could reveal improved therapeutic strategies for treating patients. Here, we report that mitochondrial metabolic pathways are suppressed in radioresistant gliomas through integrated analyses of transcrip-tomic data from glioma specimens and cell lines. Decreased expres-sion of peroxisome proliferator-activated receptor-gamma coacti-vator 1 alpha (PGC1a), the key regulator of mitochondrial bio-genesis and metabolism, correlated with glioma recurrence and predicted poor prognosis and response to radiotherapy of patients with glioma. The subpopulation of glioma cells with low-mito-chondrial-mass exhibited reduced expression of PGC1a and enhanced resistance to radiotherapy treatment. Mechanistically, PGC1a was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1a by facilitating its binding to the E3 ligase RNF34. Restoring PGC1a activity with expression of PGC1a S636A, a phosphorylation-resistant mutant, or a small -molecule PGC1a activator ZLN005 increased radiosensitivity of resistant glioma cells by reactivating mitochondria-related reactive oxygen species production and inducing apoptotic effects both in vitro and in vivo. In summary, this study identified a self -protective mechanism in glioma cells in which radiotherapy - induced degradation of PGC1a and suppression of mitochondrial biogenesis play a central role. Targeted activation of PGC1a could help improve response to radiotherapy in patients with glioma.Significance: Glioma cells reduce mitochondrial biogenesis by promoting PGC1a degradation to promote resistance to radio-therapy, indicating potential therapeutic strategies to enhance radiosensitivity.

Automated summary

Radiotherapy resistance in gliomas is a major concern. This study identified that mitochondrial metabolic pathways are suppressed in radioresistant gliomas. Decreased expression of PGC1a, a key regulator of mitochondrial biogenesis and metabolism, correlated with glioma recurrence and predicted poor prognosis and response to radiotherapy. Restoring PGC1a activity increased radiosensitivity of resistant glioma cells.