Mitochondrial glutamate transporter SLC25A22 uni-directionally export glutamate for metabolic rewiring in radioresistant glioblastoma

Glioblastoma Multiforme (GBM) is a malignant primary brain tumor. Radiotherapy, one of the standard treatments for GBM patients, could induce GBM radioresistance via rewiring cellular metabolism. However, the precise mechanism attributing to GBM radioresistance or targeting strategies to overcome GBM radioresistance are lacking. Here, we demonstrate that SLC25A22, a mitochondrial bi-directional glutamate transporter, is upregulated and showed uni-directionality from mitochondria to cytosol in radioresistant GBM cells, resulting in accumulating cytosolic glutamate. However, mitochondrial glutaminolysis-mediated TCA cycle metabolites and OCR are maintained constantly. The accumulated cytosolic glutamate enhances the glutathione (GSH) production and proline synthesis in radioresistant GBM cells. Increased GSH protects cells against ionizing radiation (IR)-induced reactive oxygen species (ROS) whereas increased proline, a rate-limiting substrate for collagen biosynthesis, induces extracellular matrix (ECM) remodeling, leading to GBM invasive phenotypes. Finally, we discover that genetic inhibition of SLC25A22 using miR-184 mimic decreases GBM radioresistance and aggressiveness both in vitro and in vivo. Collectively, our study suggests that SLC25A22 upregulation confers GBM radioresistance by rewiring glutamate metabolism, and SLC25A22 could be a significant therapeutic target to overcome GBM radioresistance.

Automated summary

This study reveals that radioresistant glioblastoma multiforme (GBM) cells exhibit upregulation of SLC25A22, a mitochondrial glutamate transporter, resulting in accumulation of cytosolic glutamate. The accumulated glutamate enhances glutathione production and proline synthesis in the cells, leading to increased resistance to ionizing radiation and a more invasive phenotype. Genetic inhibition of SLC25A22 reduces radioresistance and aggressiveness of GBM in vitro and in vivo. These findings suggest that SLC25A22 may serve as a significant therapeutic target for overcoming radioresistance in GBM.