PGC-1α degradation suppresses mitochondrial biogenesis to confer radiation resistance in glioma.

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 (PGC-1α), the key regulator of mitochondrial biogenesis and metabolism, correlated with glioma recurrence and predicted poor prognosis and response to radiation therapy of glioma patients. The subpopulation of glioma cells with low-mitochondrial-mass exhibited reduced expression of PGC-1α and enhanced resistance to radiation treatment. Mechanistically, PGC-1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase (DNA-PK) in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC-1α by facilitating its binding to the E3 ligase RNF34. Restoring PGC-1α activity with expression of PGC-1α S636A, a phosphorylation-resistant mutant, or a small molecule PGC-1α activator ZLN005 increased radiosensitivity of resistant glioma cells by reactivating mitochondria-related ROS 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 radiation-induced degradation of PGC-1α and suppression of mitochondrial biogenesis play a central role. Targeted activation of PGC-1α could help improve response to radiation therapy in glioma patients.