Golgi Stress Response, Hydrogen Sulfide Metabolism, and Intracellular Calcium Homeostasis

Abstract

Aims: The physiological and pathological importance of hydrogen sulfide (H 2 S) as a novel gasotransmitter has been widely recognized. Cystathionine gamma-lyase (CSE) is one of the major H 2 S-producing enzymes and it regulates diverse functions in connection with intracellular calcium (Ca 2+ ). The aim of this study is to examine the role of H 2 S in Golgi stress-related cell injury and skeletal muscle disorders. Results: Golgi stressors (brefeldin A [BFA] and monensin) decreased the expression of GM130 and ATP2C1 (two markers of Golgi stress response), induced Golgi apparatus fragmentation, and caused a higher level of oxidative stress and cell apoptosis in mouse myoblast cells. In addition, Golgi stressors upregulated CSE expression and endogenous H 2 S generation, and exogenously applied H 2 S was able to protect but inhibition of CSE/H 2 S system deteriorated Golgi stress response. Activating transcription factor 4 (ATF4) acted as an upstream molecule to increase CSE expression on Golgi stress response. Mechanically, Golgi stressors induced intracellular level of Ca 2+ , and chelating cellular Ca 2+ markedly attenuated Golgi stress response, indicating the key role of Ca 2+ in initiating Golgi stress and cell apoptosis. Further, administration of either angiotensin II or BFA initiated Golgi stress response and induced skeletal muscle atrophy in mice, which was further deteriorated by CSE deficiency but rescued by exogenously applied sodium hydrosulfide (NaHS). Innovation and Conclusion: The activation of the CSE/H 2 S pathway and the decrease of intracellular Ca 2+ are two cellular protective mechanisms against Golgi stress, and the CSE/H 2 S system would be a target for preventing skeletal muscle dysfunctions.