The role of the mitochondrial phosphate carrier in modulating mitochondrial homeostasis and enhancing radiosensitivity in tumor cells.

BACKGROUND

The mitochondrial phosphate carrier (PiC) is a key protein in maintaining mitochondrial homeostasis, and its dysfunction is closely associated with cell fate determination. Recent studies suggest that PiC may regulate mitochondrial permeability transition pore (MPTP) opening. However, its precise role during radiotherapy and the mechanisms by which it regulates cell death remain elusive.

METHODS AND

RESULTS

Focusing on the clinical challenge of radioresistance in glioma, this study reveals for the first time that radiation specifically suppresses PiC expression, thereby inducing mitochondrial energy metabolism failure, collapse of membrane potential, dysregulation of mtDNA replication, and significantly promoting sustained MPTP opening. Further mechanistic investigations demonstrated that this cascade of mitochondrial damage activates the mitochondrial apoptotic pathway involving Bax/Bcl-2, cytochrome c, and caspase-3, ultimately driving apoptosis in glioma cells. Consistently, concordant alterations in apoptotic markers were observed in murine tumor models, further validating these findings in vivo.

CONCLUSIONS

This study identifies PiC as a critical regulator of the radiotherapy response in glioma, demonstrating for the first time that radiation-induced PiC suppression drives apoptosis via mitochondrial dysfunction and MPTP opening. Targeting the PiC-MPTP axis represents a novel potential strategy for overcoming radioresistance and enhancing radiosensitivity in glioma.