AATF supports proliferation of glioblastoma cells by sustaining mitochondrial respiration through an NRF-1-dependent mechanism

The ability of cancer cells to promote cellular proliferation by preferentially using glycolysis as primary source of energy has long been considered a hallmark of tumour metabolism. However, emerging evidence suggests a more complex situation with many tumours exhibiting a pronounced dependence on mitochondrial respiration through oxidative phosphorylation (OXPHOS) for their development and maintenance. In line with this, numerous studies have reported an upregulation of mitochondrial genes and OXPHOS components across multiple cancer types. Glioblastoma (GBM) is the most frequent and malignant brain tumour in adults, characterised by rapid proliferation, resistance to therapy and ability to recur. In addition to a profound genetic and molecular heterogeneity, GBM also exhibits strong metabolic heterogeneity with different grades of dependence on mitochondrial activity. Notably, the transcription factor Nuclear Respiratory Factor 1 (NRF-1), a key regulator of OXPHOS gene expression and mitochondrial functions, has recently been linked to GBM progression and poor prognosis. Che-1/Apoptosis Antagonising Transcription Factor (AATF) is a transcriptional regulator with a crucial role in several cancer types, where it contributes to tumorigenesis by promoting cell cycle arrest and apoptosis, as well as resistance to therapy. Here, we show that AATF expression correlates with clinical outcome in GBM patients. Moreover, we demonstrate that its depletion leads to cell cycle arrest, impaired mitochondrial respiration and disrupted mitochondrial architecture in GBM cells. Additionally, AATF-depleted cells exhibit a reduced ability to form colonies in vitro and tumour in vivo. At the molecular level, we provide evidence that AATF interacts with NRF-1 and is essential for NRF-1-mediated transcription of the OXPHOS genes by affecting RNA polymerase II recruitment and chromatin structure. Overall, our findings highlight a previously unrecognised role of AATF in GBM proliferation and mitochondrial metabolism supporting its potential as a target for therapeutic intervention.