DMT1 ubiquitination by Nedd4 protects against ferroptosis after intracerebral hemorrhage.
CNS Neurosci Ther
; 30(4): e14685, 2024 04.
Article
de En
| MEDLINE
| ID: mdl-38634270
ABSTRACT
OBJECTIVE:
Neuronal precursor cells expressed developmentally down-regulated 4 (Nedd4) are believed to play a critical role in promoting the degradation of substrate proteins and are involved in numerous biological processes. However, the role of Nedd4 in intracerebral hemorrhage (ICH) remains unknown. This study aims to investigate the regulatory role of Nedd4 in the ICH model.METHODS:
Male C57BL/6J mice were induced with ICH. Subsequently, the levels of glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, as well as the expression of divalent metal transporter 1 (DMT1) and Nedd4 were assessed after ICH. Furthermore, the impact of Nedd4 overexpression was evaluated through analyses of hematoma area, ferroptosis, and neurobehavioral function. The mechanism underlying Nedd4-mediated degradation of DMT1 was elecidated using immunoprecipitation (IP) after ICH.RESULTS:
Upon ICH, the level of DMT1 in the brain increased, but decreased when Nedd4 was overexpressed using Lentivirus, suggesting a negative correlation between Nedd4 and DMT1. Additionally, the degradation of DMT1 was inhibited after ICH. Furthermore, it was found that Nedd4 can interact with and ubiquitinate DMT1 at lysine residues 6, 69, and 277, facilitating the degradation of DMT1. Functional analysis indicated that overexpression of Nedd4 can alleviate ferroptosis and promote recovery following ICH.CONCLUSION:
The results demonstrated that ferroptosis occurs via the Nedd4/DMT1 pathway during ICH, suggesting it potential as a valuable target to inhibit ferroptosis for the treatment of ICH.Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Hémorragie cérébrale
/
Transporteurs de cations
/
Ubiquitine protéine ligases NEDD4
/
Ferroptose
Limites:
Animals
Langue:
En
Journal:
CNS Neurosci Ther
/
CNS neurosc. ther. (Print)
/
CNS neuroscience & therapeutics (Print)
Sujet du journal:
NEUROLOGIA
/
TERAPEUTICA
Année:
2024
Type de document:
Article
Pays d'affiliation:
Chine
Pays de publication:
Royaume-Uni