Participation of Mind Bomb-2 in Sevoflurane Anesthesia Induces Cognitive Impairment in Aged Mice via Modulating Ferroptosis

Abstract

Postoperative cognitive dysfunction (POCD) is a complication of the central nervous system (CNS) often occurred after surgery or anesthesia in the elder patients. Mind bomb-2 (MIB2) has been reported to modulate neuronal functions. Here, we aimed to study whether MIB2 exerts roles in the effects of sevoflurane anesthesia on mice hippocampal neurons and function, and how. Aging male C57BL/6 mice were subjected to sevoflurane administration, and primary hippocampal neurons were adopted to study sevoflurane effects in vitro. Western blotting and immunohistochemistry assay were used to study the protein expression of MIB2. CCK-8 assay and propidium iodide (PI) staining were performed to evaluate cell viability and cell death, respectively. Ferroptosis-related indicators malondialdehyde (MDA), glutathione (GSH), and iron levels were checked through indicated ELISA kits. Co-immunoprecipitation was adopted to study the binding effects of MIB2 to GPX4. We found that sevoflurane anesthesia increased MIB2 expression in mice hippocampus tissues and neurons. Knockdown of MIB2 alleviated neuron death and ferroptosis induced by sevoflurane exposure. Downregulated MIB2 enhanced GPX4 stability and reduced its ubiquitination. MIB2 was verified to bind to GPX4. The effects of MIB2 knockdown on the neuron death and ferroptosis can be reversed by further siGPX4 transfection. In vivo results also showed that MIB2 knockdown reduced hippocampal neuron death, ferroptosis, and cognitive impairments in the sevoflurane-exposed mice. Taking all together, downregulation of MIB2 could alleviate the sevoflurane-anesthesia-induced cognitive dysfunction and neuron injury through reducing ferroptosis via GPX4. Our results also provide novel directions for POCD treatment using anti-MIB2-related drugs or strategies.

Sevoflurane Induces Ferroptosis of Glioma Cells Through Activating the ATF4-CHAC1 Pathway

“…Zhao et al. performed an in vivo experiment and certified that knockdown of neuronal regulator MIB2 could alleviate ferroptosis of neuron induced by Sev exposure ( 41 ). Our results and other studies indicated that Sev could induce ferroptosis in multiple diseases including glioma.…”

Targeting Ferroptosis by Ubiquitin System Enzymes: A Potential Therapeutic Strategy in Cancer

“…Furthermore, sevoflurane administration induces E3 ligase mind bomb 2 (MIB2) expression, thus promoting ferroptosis in hippocampal neurons. Mechanistically, MIB2 binds to GPX4 and mediates ubiquitination of GPX4 74 . Collectively, the activation of TRIM46 or MIB2 expression under different stimuli promotes GPX4 ubiquitination and ferroptosis in certain cellular contexts.…”

Ferroptosis is involved in regulating perioperative neurocognitive disorders: emerging perspectives

“…In addition, the degenerative neurological changes associated with aging make the elderly more susceptible to multifactorial stimulation of cognitive decline in the perioperative period, which can also be considered degenerative neurotoxicity. New insights suggest that ferroptosis is involved in the pathology of postoperative cognitive dysfunction [ 101 , 102 ]. The evidence from experimental studies to date is summarized in Table 1 .…”

“…In recent years, it was suggested that the E3 ubiquitin-protein ligase Mind bomb-2 (MIB2) could be involved in regulating neuronal function. In a sevoflurane-induced POCD model, knockdown of MIB2 enhanced the stability of GPX4 and reduced its ubiquitination, consequently reducing hippocampal ferroptosis [ 101 ]. The silencing of ACSL4 and MIB2 has enriched the approaches to inhibit ferroptosis in neuronal cells, and these findings provide new directions for the application of related drugs or strategies such as anti-ACSL4 and anti-MIB2 for the treatment of POCD.…”