Cystathionine γ lyase S-sulfhydrates Drp1 to ameliorate heart dysfunction

Hydrogen sulfide (H₂S), produced by cystathionine γ lyase (CSE), is an important endogenous gasotransmitter to maintain heart function. However, the molecular mechanism for how H₂S influences the mitochondrial morphology during heart failure remains poorly understood. Here, we found that CSE/H₂S pathway mediated cardiac function and mitochondrial morphology through regulating dynamin related protein 1 (Drp1) activity and translocation. Mechanistically, elevation of H₂S levels by CSE overexpression declined protein level, phosphorylation (Ser 616), oligomerization and GTPase activity of Drp1 by S-sulfhydration in mouse hearts. Interestingly, Drp1 S-sulfhydration directly competed with S-nitrosylation by nitric oxide at the specific cysteine 607. The non-S-sulfhydration of Drp1 mutation (C607A) attenuated the regulatory effect of H₂S on Drp1 activation, mitochondrial fission and heart function. Moreover, the non-canonical role of Drp1 mediated isoprenaline-induced mitochondrial dysfunction and cardiomyocyte death through interaction with voltage-dependent anion channel 1. These results uncover that a novel mechanism that H₂S S-sulfhydrated Drp1 at cysteine 607 to prevent heart failure through modulating its activity and mitochondrial translocation. Our findings also provide initial evidence demonstrating that Drp1 may be a critical regulator as well as an effective strategy for heart dysfunction.