AUTHOR=Xiao Tingting , Chen Shun , Yan Ge , Zheng Junmin , Qiu Qingzhu , Lin Shujia , Zong Yanfang , Chang Haishuang , Yu Chang Alex Chia , Wu Ying , Hou Cuilan TITLE=Cystathionine γ-lyase inhibits mitochondrial oxidative stress by releasing H2S nearby through the AKT/NRF2 signaling pathway JOURNAL=Frontiers in Pharmacology VOLUME=Volume 15 - 2024 YEAR=2024 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1374720 DOI=10.3389/fphar.2024.1374720 ISSN=1663-9812 ABSTRACT=Cystathionine γ-lyase (CSE), is a major hydrogen sulfide (H2S) producing-enzyme. Herein, we reported that CSE plays a previously unknown role in regulating the antioxidant effects of human umbilical vein endothelial cells mitochondria by releasing H2S nearby in stress conditions. We found that H2S partially promoted angiogenesis in endothelial cells through the AKT/nuclear factor erythroid 2-related factor 2 signaling pathway. H2S improved mitochondrial function by altering the expression of the mitochondrial fission proteins mitofusin2, dynamin-1-like, inhibiting oxidative stress, and enhancing nuclear factor erythroid 2-related factor 2 nuclear translocation. CSE is only located in the cytoplasm and not in the mitochondria, and is transported to the vicinity of the mitochondria to produce H2S, which plays an antioxidant role in human umbilical vein endothelial cells under stress. The CSE mutant (CSE activity center was mutated: CSED187A) partially decreased its effects on promoting angiogenesis, resisting oxidative stress, and entering the mitochondria. These results revealed that CSE translocation is a unique mechanism that promotes H2S production inside mitochondria under stress stimulation. Therefore, the CSE mutant site (CSED187A) may be a potential target for drug therapy.