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

Area of Science:

• Cell Biology
• Molecular Biology
• Rheumatology

Background:

• Rheumatoid arthritis (RA) involves fibroblast-like synoviocytes (FLSs) and mitochondrial dysfunction.
• Oxidative stress plays a key role in RA pathogenesis.
• The role of macrophage stimulating 1 (Mst1) and AMPK-Sirt1 pathway in RA-FLS is not fully understood.

Purpose of the Study:

• To investigate the role of Mst1 and the AMPK-Sirt1 signaling pathway in oxidative stress-induced mitochondrial dysfunction and apoptosis in RA-FLSs.
• To explore the potential of targeting the Mst1-AMPK-Sirt1 axis for RA therapy.

Main Methods:

• RA-FLSs were treated with hydrogen peroxide (H2O2) to induce oxidative stress.
• Mst1 expression and function were modulated using silencing techniques.
• Mitochondrial function, apoptosis markers (caspase3/9, Bax), reactive oxygen species (ROS), and mitochondrial membrane potential were assessed.
• The impact of Sirt1 inhibition (selisistat) and AMPK antagonism (compound C) was evaluated.

Main Results:

• H2O2 treatment upregulated Mst1, induced apoptosis, and impaired mitochondrial function (reduced membrane potential and respiration, increased ROS) in RA-FLSs.
• Mst1 silencing significantly attenuated H2O2-induced mitochondrial dysfunction and apoptosis.
• Sirt1 expression was reduced by H2O2 but increased upon Mst1 silencing.
• Inhibiting Sirt1 or AMPK exacerbated mitochondrial dysfunction and reduced viability in Mst1-silenced, H2O2-treated RA-FLSs.

Conclusions:

• Oxidative stress upregulates Mst1, which promotes mitochondrial dysfunction and apoptosis in RA-FLSs by inhibiting the AMPK-Sirt1 pathway.
• The Mst1-AMPK-Sirt1 axis represents a promising therapeutic target for rheumatoid arthritis.