Regulation of the oxidative stress response is crucial for the management and prognosis of traumatic brain injury (TBI). The copper chaperone Antioxidant 1 (Atox1) plays a crucial role in regulating intracellular copper ion balance and impacting the antioxidant capacity of mitochondria, as well as the oxidative stress state of cells. However, it remains unknown whether Atox1 is involved in modulating oxidative stress following TBI. Here, we investigated the regulatory role of Atox1 in oxidative stress on neurons both in vivo and in vitro, and elucidated the underlying mechanism through culturing hippocampal HT-22 cells with Atox1 mutation. The expression of Atox1 was significantly diminished following TBI, while mice with overexpressed Atox1 exhibited a more preserved hippocampal structure and reduced levels of oxidative stress post-TBI. Furthermore, the mice displayed notable impairments in learning and memory functions after TBI, which were ameliorated by the overexpression of Atox1. In the stretch injury model of HT-22 cells, overexpression of Atox1 mitigated oxidative stress by preserving the normal morphology and network connectivity of mitochondria, as well as facilitating the elimination of damaged mitochondria. Mechanistically, co-immunoprecipitation and mass spectrometry revealed the binding of Atox1 to DJ-1. Knockdown of DJ-1 in HT-22 cells significantly impaired the antioxidant capacity of Atox1. Mutations in the copper-binding motif or sequestration of free copper led to a substantial decrease in the interaction between Atox1 and DJ-1, with overexpression of DJ-1 failing to restore the antioxidant capacity of Atox1 mutants. The findings suggest that DJ-1 mediates the ability of Atox1 to withstand oxidative stress. And targeting Atox1 could be a potential therapeutic approach for addressing post-traumatic neurological dysfunction.
Brain Injuries, Traumatic , Copper Transport Proteins , Hippocampus , Mitophagy , Neurons , Oxidative Stress , Protein Deglycase DJ-1 , Animals , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/pathology , Brain Injuries, Traumatic/genetics , Mice , Hippocampus/metabolism , Hippocampus/pathology , Neurons/metabolism , Protein Deglycase DJ-1/metabolism , Protein Deglycase DJ-1/genetics , Copper Transport Proteins/metabolism , Copper Transport Proteins/genetics , Mitochondria/metabolism , Disease Models, Animal , Molecular Chaperones/metabolism , Molecular Chaperones/genetics , Male , Antioxidants/metabolism , Cell Line , Humans
The oncogene Aurora kinase A (AURKA) has been implicated in various tumor, yet its role in meningioma remains unexplored. Recent studies have suggested a potential link between AURKA and ferroptosis, although the underlying mechanisms are unclear. This study presented evidence of AURKA upregulation in high grade meningioma and its ability to enhance malignant characteristics. We identified AURKA as a suppressor of erastin-induced ferroptosis in meningioma. Mechanistically, AURKA directly interacted with and phosphorylated kelch-like ECH-associated protein 1 (KEAP1), thereby activating nuclear factor erythroid 2 related factor 2 (NFE2L2/NRF2) and target genes transcription. Additionally, forkhead box protein M1 (FOXM1) facilitated the transcription of AURKA. Suppression of AURKA, in conjunction with erastin, yields significant enhancements in the prognosis of a murine model of meningioma. Our study elucidates an unidentified mechanism by which AURKA governs ferroptosis, and strongly suggests that the combination of AURKA inhibition and ferroptosis-inducing agents could potentially provide therapeutic benefits for meningioma treatment.
Aurora Kinase A , Ferroptosis , Forkhead Box Protein M1 , Meningioma , NF-E2-Related Factor 2 , Piperazines , Ferroptosis/drug effects , Ferroptosis/genetics , Forkhead Box Protein M1/metabolism , Forkhead Box Protein M1/genetics , Aurora Kinase A/metabolism , Aurora Kinase A/genetics , Humans , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Animals , Mice , Meningioma/metabolism , Meningioma/genetics , Meningioma/pathology , Piperazines/pharmacology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/drug effects , Signal Transduction/drug effects , Kelch-Like ECH-Associated Protein 1/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , Meningeal Neoplasms/metabolism , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meningeal Neoplasms/drug therapy , Drug Resistance, Neoplasm/genetics
The molecular mechanism of glioblastoma (GBM) radiation resistance remains poorly understood. The aim of this study was to elucidate the potential role of Melanophilin (MLPH) O-GlcNAcylation and the specific mechanism through which it regulates GBM radiotherapy resistance. We found that MLPH was significantly upregulated in recurrent GBM tumor tissues after ionizing radiation (IR). MLPH induced radiotherapy resistance in GBM cells and xenotransplanted human tumors through regulating the NF-κB pathway. MLPH was O-GlcNAcylated at the conserved serine 510, and radiation-resistant GBM cells showed higher levels of O-GlcNAcylation of MLPH. O-GlcNAcylation of MLPH protected its protein stability and tripartite motif containing 21(TRIM21) was identified as an E3 ubiquitin ligase promoting MLPH degradation whose interaction with MLPH was affected by O-GlcNAcylation. Our data demonstrate that MLPH exerts regulatory functions in GBM radiation resistance by promoting the NF-κB signaling pathway and that O-GlcNAcylation of MLPH both stabilizes and protects it from TRIM21-mediated ubiquitination. These results identify a potential mechanism of GBM radiation resistance and suggest a potential therapeutic strategy for GBM treatment.
Glioblastoma , NF-kappa B , Humans , NF-kappa B/genetics , Cell Line, Tumor , Glioblastoma/genetics , Glioblastoma/radiotherapy , Glioblastoma/pathology , Neoplasm Recurrence, Local , Ubiquitination
