GSDME-N Exacerbates Its Cytotoxicity by Upregulating Mitochondrial Aggregation of BAX
10.13865/j.cnki.cjbmb.2025.08.1159
- VernacularTitle:GSDME-N通过上调BAX向线粒体的聚集而加剧其细胞毒性
- Author:
Sai-Tao QIU
1
;
Jun-Jun ZHAO
;
Xiao-Xi REN
;
Li-Rong ZHANG
;
Tai ZHOU
;
Jian-Liang ZHANG
Author Information
1. 首都医科大学基础医学院神经生物学系,北京 100069
- Publication Type:Journal Article
- Keywords:
Parkinson's disease(PD);
mitochondrion;
pyroptosis;
gasdermin(GSDME)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(11):1668-1677
- CountryChina
- Language:Chinese
-
Abstract:
Parkinson's disease(PD)is one of the most common neurodegenerative disorders.Recent evidence implicates pyroptosis as one of the pathogenic mechanisms in central nervous system disorders,although its specific mechanisms remain unclear.In this study,SH-SY5Y cells were transfected with py-roptosis-related proteins GSDME full-length(GSDME-F)or GSDME-N terminal(GSDME-N)plasmids revealed that GSDME-N significantly reduced mitochondrial membrane potential(P＜0.0001).To inves-tigate the mechanism by which GSDME mediates mitochondrial dysfunction,Western blotting analysis demonstrated that transfection with GSDME-N plasmids significantly increased BAX expression and en-hanced its translocation to mitochondria in both HEK 293T and SH-SY5Y cells(P＜0.05).SH-SY5Y cells treated with varying concentrations of rotenone(ROT)exhibited GSDME cleavage,elevated BAX expression(P＜0.05),increased mitochondrial BAX aggregation(P＜0.05),and reduced mitochondrial membrane potential(P＜0.01),as confirmed by Western blotting and JC-1 staining.Concurrently,MTT assays assessing cell viability and lactate dehydrogenase(LDH)release assays indicated that ROT in-duced these processes prior to pyroptosis.Furthermore,in a ROT-induced mouse PD model,ROT trig-gered GSDME cleavage,enhanced BAX expression,caused dopaminergic neuronal damage,and induced motor deficits.In summary,this study demonstrates that GSDME-N exacerbates mitochondrial damage and increases cytotoxicity by upregulating BAX expression and facilitating its mitochondrial translocation.This study provides novel insights into the role of GSDME in PD pathogenesis and suggests potential avenues for therapeutic intervention.
