Xiao Tingting, Chen Shun, Yan Ge, Zheng Junmin, Qiu Qingzhu, Lin Shujia, Zong Yanfang, Chang Haishuang, Yu Chang Alex Chia, Wu Ying, Hou Cuilan
Department of Cardiology, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Pediatric Allergy and Immune Disease Laboratory, Kawasaki Disease Research Center, NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology, Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, China.
Shanghai Institute Precision Medicine, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai, Shanghai, China.
Front Pharmacol. 2024 Jul 23;15:1374720. doi: 10.3389/fphar.2024.1374720. eCollection 2024.
Cystathionine γ-lyase (CSE) is a major enzyme that produces hydrogen sulfide (HS). Herein, we report how CSE plays a previously unknown role in regulating the antioxidant effects of the mitochondria in human umbilical vein endothelial cells by releasing HS nearby under stress conditions. We found that HS partially promoted angiogenesis in the endothelial cells through the AKT/nuclear factor erythroid 2-related factor 2 (AKT/NRF2) signaling pathway. HS improved mitochondrial function by altering the expressions of the mitofusin2 and dynamin-1-like mitochondrial fission proteins to inhibit oxidative stress and enhance NRF2 nuclear translocation. CSE is located only in the cytoplasm and not in the mitochondria, but it is transported to the vicinity of the mitochondria to produce HS, which plays an antioxidant role in human umbilical vein endothelial cells under stress. The CSE mutant (with mutated CSE activity center: CSE) partially decreased the effects on promoting angiogenesis, resisting oxidative stress, and entering the mitochondria. These results show that CSE translocation is a unique mechanism that promotes HS production inside the mitochondria under stress stimulation. Therefore, the CSE mutant site (CSE) may be a potential target for drug therapy.
胱硫醚γ-裂解酶（CSE）是产生硫化氢（HS）的一种主要酶。在此，我们报告了CSE如何通过在应激条件下于线粒体附近释放HS，在调节人脐静脉内皮细胞中线粒体的抗氧化作用方面发挥了先前未知的作用。我们发现HS通过AKT/核因子红细胞2相关因子2（AKT/NRF2）信号通路部分促进内皮细胞中的血管生成。HS通过改变线粒体融合蛋白2和动力蛋白样线粒体分裂蛋白的表达来改善线粒体功能，以抑制氧化应激并增强NRF2核转位。CSE仅位于细胞质中而非线粒体中，但它被转运到线粒体附近以产生HS，HS在应激条件下的人脐静脉内皮细胞中发挥抗氧化作用。CSE突变体（具有突变的CSE活性中心：CSE）部分降低了对促进血管生成、抵抗氧化应激和进入线粒体的作用。这些结果表明，CSE易位是一种在应激刺激下促进线粒体内部产生HS的独特机制。因此，CSE突变位点（CSE）可能是药物治疗的潜在靶点。
