PGC1-α drives MFN2-linked mitochondrial fusion aiding glioblastoma cell survival under TMZ stress

Abstract

Glioblastoma Multiforme (GBM) is an extremely aggressive primary brain-tumor with a median-survival rate of <2 years. Higher risk in surgery has shifted the treatment paradigm towards combined chemotherapies. Interestingly, arduous dependency on chemotherapy has shown recurrence. Recent studies have portrayed the role of mitochondrial dynamics for survival under drug-pressure leading to recurrence. However, such studies exploring the role of mitochondria in response to drug stress in GBM are limited. Here we show that PGC1α (Peroxisome Proliferator-activated Receptor Gamma coactivator-1 Alpha) upregulates Mfn2 (Mitofusin 2) enhancing mitochondrial-fusion in GBM cells contributing to survival under profound Temozolomide (TMZ) stress. The interaction of PGC1α with SET1 compass / compass-like complex induces H3K4me3 trimethylations at the promoter regions of Mfn2 leading to an open chromatin assisting Mfn2 upregulation. The latter is further involved in inducing mitochondrial fusion, promoting oxidative phosphorylation which supports cell survival under stress. Notably, this further corroborates with our observations in the patient samples and clinical data where upregulation of Mfn2 was concurrently observed with elevated levels of PGC1α simultaneously leading to poor prognosis. Thus, this study provides critical insights into the molecular regulation of mitochondrial dynamics-dependent survival mechanisms in GBM that could further be exploited to design future therapies.