FBXL4靶向调控Drp1介导的线粒体动力学抑制氧化应激和凋亡保护心肺复苏后脑损伤的机制

doi:10.3969/j.issn.1006-5725.2026.14.002

Abstract

Abstract:

Objective To explore the molecular mechanism by which F-box/leucine-rich repeat protein 4 （FBXL4） inhibits oxidative stress and apoptosis， and prevents cerebral ischemia-reperfusion injury （CIRI） induced by cardiopulmonary resuscitation （CPR） after cardiac arrest （CA） through regulating dynamin-related protein 1 （Drp1）-mediated mitochondrial dynamics. Methods A total of 48 male SD rats were randomly divided into 4 groups， with 6 rats in each group （n = 6）： Control group， Control + FBXL4 overexpression （OE-FBXL4） group， CA/CPR group， and CA/CPR + OE-FBXL4 group. Survival analysis was also conducted， with 6 cases in each group. The rats were sacrificed at 24 h after the return of spontaneous circulation （ROSC） for sampling. The neurological deficit score （NDS） and the 7-day survival rate were detected. The expressions of FBXL4 and Drp1 mRNA and proteins were determined by RT-qPCR and Western blot. The expressions of mitochondrial dynamics proteins were measured by Western blot. The interaction between FBXL4 and Drp1 was verified by the co-immunoprecipitation method. The pathology of brain tissues was examined by HE staining and Nissl staining. The ultrastructure of mitochondria was observed using a transmission electron microscope. The levels of malondialdehyde （MDA）， superoxide dismutase （SOD）， glutathione （GSH）， and catalase （CAT） were measured by a biochemical method to evaluate the oxidative stress level. The expressions of apoptosis-related proteins ［B cell lymphoma-2 associated X protein （Bax）， B cell lymphoma-2 （Bcl-2）， cysteine aspartase peptidases （Caspase）-3/8］ were measured by Western blot. Results （1） When compared to the Control group， the Neurological Deficit Score （NDS） in the CA/CPR group was significantly lower （P < 0.01）， and the 7-day survival rate was also reduced. In the brain tissues， the expressions of FBXL4 mRNA and protein were significantly down-regulated （all P < 0.01）， while the expressions of Drp1， Fis1， and MFF were significantly up-regulated （all P < 0.01）， and the expressions of OPA1， MFN1， and MFN2 were significantly down-regulated （all P < 0.01）. HE and Nissl staining results indicated that in the cortex and the CA1 and CA3 regions of the hippocampus， neurons were arranged in a disordered manner， with cell body atrophy， dissolution of Nissl bodies， and a decreased number of surviving neurons. Transmission electron microscopy （TEM） revealed mitochondrial swelling， vacuolization， cristae fracture， and fragmentation. The content of MDA was increased （P < 0.01）， whereas the activities of SOD， GSH， and CAT were decreased （all P < 0.01）. The Bax/Bcl-2 ratio was elevated （P < 0.01）， and the expressions of Caspase-3 and Caspase-8 were increased （both P < 0.01）. （2） In comparison with the CA/CPR group， the Neurological Deficit Score （NDS） was significantly elevated in the CA/CPR + OE-FBXL4 group （P < 0.01）， and the 7-day survival rate was also significantly increased. The expression of the FBXL4 protein was at a high level. The levels of Drp1， Fis1， and MFF proteins decreased （all P < 0.01）， while the levels of OPA1， MFN1， and MFN2 proteins increased （all P < 0.01）. HE and Nissl staining indicated an improvement in neuronal morphology， a reduction in the number of degenerated and necrotic cells， and an increase in the number of survived neurons. Transmission electron microscopy （TEM） revealed the recovery of the mitochondrial pipe-network structure and a clear and complete cristae structure. The content of MDA decreased （P < 0.01）， and the activities of SOD， GSH， and catalase （CAT） increased （all P < 0.01）. The Bax/Bcl-2 ratio decreased （P < 0.01）， and the expressions of Caspase-3 and Caspase-8 decreased （both P < 0.01）. （3） A Co-IP experiment confirmed a protein-protein interaction between FBXL4 and Drp1. The formation amount of the FBXL4-Drp1 complex in the Control + OE-FBXL4 group was significantly higher than that in the Control group （P < 0.01）. The formation amount of the FBXL4-Drp1 complex decreased in the CA/CPR group， and the binding amount was significantly restored in the CA/CPR + OE-FBXL4 group. Conclusions FBXL4 serves as a crucial protective regulator against brain injury following CA/CPR. The overexpression of FBXL4 can restore mitochondrial dynamic balance by targeting Drp1， thus suppressing oxidative stress and neuronal apoptosis. Moreover， the further up-regulation of the Nrf2/HO-1 pathways may be synergistically involved in the antioxidant protection provided by FBXL4.

Key words: FBXL4, mitochondrial dynamics, cardiopulmonary resuscitation, cerebral ischemia-reperfusion injury, oxidative stress, apoptosis

CLC Number:

R541.7

Xiaolu JIANG,Hongfu WEN,Yuan SHEN,Jun ZHANG,Lini LI,Renlu XU,Wen ZHANG,Xiaoming WANG,Yifei JI,Weidong LI. Mechanism of FBXL4 inhibiting oxidative stress and apoptosis， and preventing brain injury after cardiopulmonary resuscitation by regulating Drp1-mediated mitochondrial dynamics[J]. The Journal of Practical Medicine, 2026, 42(14): 2488-2504.

Figures/Tables 9

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Mechanism of FBXL4 inhibiting oxidative stress and apoptosis， and preventing brain injury after cardiopulmonary resuscitation by regulating Drp1-mediated mitochondrial dynamics

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