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. 2025 Jan 2;16:276. doi: 10.1038/s41467-024-55661-5

Fig. 7. Cys644 bulkiness mediated Glu640-Ser637 interaction regulates hypoxia-induced Drp1 activation.

Fig. 7

A The GTP-binding activity of exogenous FLAG-Drp1 mutant under normoxia (Nor) or hypoxia (Hyp) (n = 3 independent experiments). WT: wild-type, CW: C644W, CS: C644S, EA: E640A, EA CW: E640A C644W, EA CS: E640A C644S. B Effect of E640A mutation on hypoxia-mediated interaction between FLNa and FLAG-Drp1. FLAG-Drp1 was immunoprecipitated from 293 T cells transfected with FLAG-Drp1 WT or EA (n = 3 independent experiments). C Structural dynamic comparison of variable domain (VD) among CysSH, CysSSH and EA was analyzed using principal component analysis (PCA). D Schematic of supersulfide catabolism-mediated mitochondrial fission and its protective role by GSSG. Electrons from mitochondrial ETC under hypoxia mediate catabolism of the polysulfide group at Drp1 Cys644 (Cys644-S(n)SH, n ≥ 1). Depolysulfidated Drp1 induces mitochondrial fission through Drp1-FLNa-Actin complex formation, resulting in myocardial dysfunction. GSSG mediates S-glutathionylation of Drp1 at Cys644, preventing supersulfide catabolism-induced mitochondrial fission. Data are shown as the means ± SEM. Significance was determined by one-way ANOVA followed by Tukey’s post-hoc test A. Source data are provided as a Source Data file.