PGC1α Degradation Suppresses Mitochondrial Biogenesis to Confer Radiation Resistance in Glioma

Abstract Radiotherapy is a major component of standard-of-care treatment 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 transcriptomic data from glioma specimens and cell lines. Decreased expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α), the key regulator of mitochondrial biogenesis 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-mitochondrial-mass exhibited reduced expression of PGC1α and enhanced resistance to radiotherapy treatment. Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34. Restoring PGC1α activity with expression of PGC1α S636A, a phosphorylation-resistant mutant, or a small-molecule PGC1α 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 PGC1α and suppression of mitochondrial biogenesis play a central role. Targeted activation of PGC1α could help improve response to radiotherapy in patients with glioma. Significance: Glioma cells reduce mitochondrial biogenesis by promoting PGC1α degradation to promote resistance to radiotherapy, indicating potential therapeutic strategies to enhance radiosensitivity.