OMA1 maintains the stemness of glioma stem cells by inducing mitochondrial fission/fusion imbalance

Abstract

Background: Cancer stem cells (CSCs) are the main cause of tumorigenesis, recurrence, and drug resistance and ultimately result in poor clinical outcomes. An imbalance in mitochondrial dynamics is an important manifestation of tumorigenesis. Based on increasing evidence, excessive fission and reduced fusion are common features of many tumors. However, the precise functions and underlying molecular mechanisms of OMA1 in the regulation of mitochondrial homeostasis for CSCs remain unknown. Methods: High-throughput sequencing and bioinformatics were used to select the target molecule, OMA1, and the expression and prognostic significance of OMA1 were analyzed in patients with glioma using data from The Cancer Genome Atlas. The role of OMA1 in regulating mitophagy in gliomas was evaluated in vitro and in vivo. OMA1 expression in clinical glioma specimens was evaluated using western blotting and immunohistochemistry. Results: Glioma stem cells had higher OMA1 expression and distinct mitochondrial morphology than differentiated tumor cells. OMA1 mediated mitochondrial fission, induced mitophagy in tumor cells, and promoted glioma stem cell stemness maintenance via mitophagy. Interestingly, glioma stem cells displayed a unique oxidative phosphorylation dependence. OMA1 promoted tumor progression in glioma cells in vitro and in vivo. Mechanistically, OMA1 promoted mitophagy and maintained Pink1 stability through the Pink1/Parkin signaling pathway. Finally, OMA1 promoted tumor immune escape by upregulating PD-L1 expression. Conclusion: OMA1 promotes phenotype maintenance of glioma stem cells by regulating oxidative phosphorylation homeostasis through the Pink1-Parkin-ROS axis. Overall, OMA1 may be beneficial as a therapeutic strategy for gliomas.