Molecular biology reports · 2024
Mdivi-1 alleviates ferroptosis induced by hypoxia combined with propofol in HT22 cells by inhibiting excessive mitophagy.
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Yang Shun, Xu Yao, Ahmad Tauseef, Deng Qianyu, Gan Zhengwei, Yang Ying, Yun Huanjie, Dong Zhifang, Tu Shengfen
Аннотация
BACKGROUND: Pediatric postoperative cognitive dysfunction (POCD) is a prevalent complication following anesthesia and surgery. Hypoxia and propofol are the primary risk factors contributing to pediatric POCD. Our previous in vivo animal research has demonstrated that cognitive dysfunction in immature Sprague-Dawley (SD) rats, induced by hypoxia combined with propofol (HCWP), is closely associated with hippocampal neuron ferroptosis.
METHODS AND RESULTS: In vivo transcriptome sequencing and KEGG functional analysis revealed significant enrichment of the mitophagy pathway. To further elucidate the relationship between mitophagy and ferroptosis, HT22 cells were selected to construct an in vitro HCWP model. Our findings indicate that HCWP activates excessive mitophagy in HT22 cells, leading to decreased mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) burst, mitochondrial fragmentation, and the induction of ferroptosis. To explore this causal relationship further, we employed Mdivi-1, a mitophagy inhibitor. Notably, low-dose Mdivi-1 (10 µM) effectively suppressed excessive mitophagy in HT22 cells, improved mitochondrial function and morphology, and mitigated markers associated with ferroptosis. The mechanism by which Mdivi-1 alleviates HCWP-induced ferroptosis in HT22 cells is likely due to its inhibition of excessive mitophagy, thereby promoting mitochondrial homeostasis.
CONCLUSIONS: Our study suggests that mitophagy may be an upstream event in HCWP-induced ferroptosis in HT22 cells. Consequently, targeted regulation of mitophagy by Mdivi-1 may represent a promising approach to prevent cognitive dysfunction following HCWP exposure.
METHODS AND RESULTS: In vivo transcriptome sequencing and KEGG functional analysis revealed significant enrichment of the mitophagy pathway. To further elucidate the relationship between mitophagy and ferroptosis, HT22 cells were selected to construct an in vitro HCWP model. Our findings indicate that HCWP activates excessive mitophagy in HT22 cells, leading to decreased mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) burst, mitochondrial fragmentation, and the induction of ferroptosis. To explore this causal relationship further, we employed Mdivi-1, a mitophagy inhibitor. Notably, low-dose Mdivi-1 (10 µM) effectively suppressed excessive mitophagy in HT22 cells, improved mitochondrial function and morphology, and mitigated markers associated with ferroptosis. The mechanism by which Mdivi-1 alleviates HCWP-induced ferroptosis in HT22 cells is likely due to its inhibition of excessive mitophagy, thereby promoting mitochondrial homeostasis.
CONCLUSIONS: Our study suggests that mitophagy may be an upstream event in HCWP-induced ferroptosis in HT22 cells. Consequently, targeted regulation of mitophagy by Mdivi-1 may represent a promising approach to prevent cognitive dysfunction following HCWP exposure.