Mst1 promotes mitochondrial dysfunction and apoptosis in oxidative stress-induced rheumatoid arthritis synoviocytes

Abstract

In this study, we investigated the role of macrophage stimulating 1 (Mst1) and the AMPK-Sirt1 signaling pathway in the oxidative stress-induced mitochondrial dysfunction and apoptosis seen in rheumatoid arthritis-related fibroblast-like synoviocytes (RA-FLSs). Mst1 mRNA and protein expression was significantly higher in hydrogen peroxide (H 2 O 2 )-treated RA-FLSs than untreated controls. H 2 O 2 treatment induced the mitochondrial apoptotic pathway by activating caspase3/9 and Bax in the RA-FLSs. Moreover, H 2 O 2 treatment significantly reduced mitochondrial membrane potential and mitochondrial state-3 and state-4 respiration, but increased reactive oxygen species (ROS). Mst1 silencing significantly reduced oxidative stress-induced mitochondrial dysfunction and apoptosis in RA-FLSs. Sirt1 expression was significantly reduced in the H 2 O 2 -treated RA-FLSs, but was higher in the H 2 O 2 -treated Mst1-silenced RA-FLSs. Pretreatment with selisistat (Sirt1-specific inhibitor) or compound C (AMPK antagonist) significantly reduced the viability and mitochondrial function in H 2 O 2 -treated Mst1-silenced RA-FLSs by inhibiting Sirt1 function or Sirt1 expression, respectively. These findings demonstrate that oxidative stress-related upregulation and activation of Mst1 promotes mitochondrial dysfunction and apoptosis in RA-FLSs by inhibiting the AMPK-Sirt1 signaling pathway. This suggests the Mst1-AMPK-Sirt1 axis is a potential target for RA therapy.

cGAS/STING signaling in the regulation of rheumatoid synovial aggression

“…In our study, we found that cGAS or STING knockdown reduced ROS production and that a mitochondrial ROS inhibitor diminished the phosphorylation of MST1 in ISD dsDNA-stimulated RA FLSs. Consistent with our findings, a previous study showed that oxidative stress stimulation increased MST1 expression and promoted mitochondrial dysfunction in RA FLSs (13). We also observed that a mitochondrial ROS inhibitor reduced ISD dsDNA-induced migration and invasion of RA FLSs.…”

“…We next sought to gain mechanistic insights into how cGAS/ STING modulates MST1 expression in RA FLSs. It has been reported that MST1 is sensitive to oxidative stress (13); therefore, we investigated whether reactive oxygen species (ROS) production is involved in the role of cGAS/STING in controlling MST1. 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) was used to measure the ROS production.…”

AMPK-SIRT1 Pathway Modulates The Apoptosis, Proliferation and Migration of AR42J Cells By Regulating p53 and NF-κB

“…SIRT1 is a downstream effector of AMPK, and shares common characteristics with AMPK in metabolism and cell survival [9] . A large number of studies have indicated that AMPK-SIRT1 pathway is involved in a variety of diseases, including cerebral ischemic stroke, liver cancer, diabetic nephropathy, rheumatoid arthritis, sepsis, and Alzheimer's disease [14,15,23,24,25] . However, the role of AMPK-SIRT1 pathway in AP has not been determined, which remains to be investigated.…”

Glycolysis Rate-Limiting Enzymes: Novel Potential Regulators of Rheumatoid Arthritis Pathogenesis

“…SUMOylation occurs through a series of stress-induced biochemical responses (132). Oxidative stress is a contributing factor in the pathogenesis of RA and influences the development of the RA process through multiple pathways (133,134). RA as an autoimmune disease and SUMOylation is a novel pathway involving its phenotypic differences (135) and ubiquitin like modifier activating enzyme 2 (UBA2) in FLSs and ST of patients with RA, where SAE1/UBA2 regulated the glycolytic pathway and biological functions of the RA FLSs through SUMOylation-mediated PKM2 phosphorylation (123).…”

“…SUMOylation occurs through a series of stress-induced biochemical responses ( 132 ). Oxidative stress is a contributing factor in the pathogenesis of RA and influences the development of the RA process through multiple pathways ( 133 , 134 ). RA as an autoimmune disease and SUMOylation is a novel pathway involving its phenotypic differences ( 135 ).…”