Mitochondrial dysfunction regulates the JAK-STAT pathway via LKB1-mediated AMPK activation ER-stress-independent...

Area of Science:

• Cell Biology
• Immunology
• Mitochondrial Biology

Background:

• Mitochondria and endoplasmic reticulum (ER) interact physically and functionally.
• Mitochondrial dysfunction (MD) and ER stress can impact cellular inflammatory responses.
• The role of combined MD and ER stress in macrophage proinflammatory activities requires clarification.

Purpose of the Study:

• To investigate the combined effects of MD and ER stress on the proinflammatory activities of macrophages.
• To define the specific pathways involved in MD-induced modulation of interferon-gamma (IFN-γ) signaling.

Main Methods:

• THP-1 cells were treated with mitochondrial electron transport chain (ETC) blockers to induce MD.
• Cellular responses to IFN-γ stimulation were analyzed, focusing on JAK-STAT pathway activation.
• Pharmacological modulators of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and LKB1-deficient cells were used to elucidate the mediating pathway.
• ER stress sensors were pharmacologically inhibited to assess their involvement.

Main Results:

• MD induced by ETC blockers suppressed IFN-γ-induced activation of JAK1 and STAT1/3.
• Expression of STAT1-regulated genes was also reduced under MD conditions.
• The suppressive effects were mediated by the liver kinase B1 (LKB1)-AMPK pathway.
• Inhibition of ER stress sensors did not affect these MD-induced suppressive processes.

Conclusions:

• MD, induced by ETC blockers, inhibits IFN-γ-induced JAK-STAT activation and associated inflammatory changes in THP-1 cells.
• The LKB1-AMPK pathway is the key mediator of these suppressive effects.
• ER stress is not required for MD to affect IFN-γ signaling in this context.