Department of Anesthesiology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China.
Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Mol Biol Rep. 2024 Jul 30;51(1):870. doi: 10.1007/s11033-024-09812-y.
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.
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.
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.
儿科术后认知功能障碍（POCD）是麻醉和手术后普遍存在的并发症。缺氧和丙泊酚是导致儿科 POCD 的主要危险因素。我们之前的体内动物研究表明，缺氧联合丙泊酚（HCWP）诱导的未成熟 Sprague-Dawley（SD）大鼠认知功能障碍与海马神经元铁死亡密切相关。
体内转录组测序和 KEGG 功能分析显示，自噬途径显著富集。为了进一步阐明自噬与铁死亡之间的关系，选择 HT22 细胞构建体外 HCWP 模型。我们的研究结果表明，HCWP 激活 HT22 细胞中过度的自噬，导致线粒体膜电位（ΔΨm）下降、活性氧（ROS）爆发、线粒体碎片化和铁死亡的诱导。为了进一步探讨这种因果关系，我们使用了 Mdivi-1，一种自噬抑制剂。值得注意的是，低剂量 Mdivi-1（10 µM）可有效抑制 HT22 细胞中过度的自噬，改善线粒体功能和形态，并减轻与铁死亡相关的标志物。Mdivi-1 减轻 HT22 细胞中 HCWP 诱导的铁死亡的机制可能是通过抑制过度自噬，从而促进线粒体稳态。
我们的研究表明，自噬可能是 HT22 细胞中 HCWP 诱导铁死亡的上游事件。因此，通过 Mdivi-1 靶向调节自噬可能是预防 HCWP 暴露后认知功能障碍的一种有前途的方法。
