CLUH functions as a negative regulator of inflammation in human macrophages and determines ulcerative colitis...

Area of Science:

• Immunology
• Cell Biology
• Gastroenterology

Background:

• Altered mitochondrial function is observed in ulcerative colitis (UC) patients.
• The specific molecular mechanisms underlying these mitochondrial alterations in UC remain unclear.

Purpose of the Study:

• To investigate the role of clustered mitochondrial homolog (CLUH) in the pathogenesis of ulcerative colitis (UC).
• To elucidate the mechanisms by which CLUH influences macrophage function and inflammation in UC.

Main Methods:

• Reduced CLUH expression was analyzed in UC tissues and human macrophages stimulated with Toll-like receptor (TLR) ligands.
• The interaction between CLUH and dynamin-related protein 1 (DRP1) was examined.
• Mitochondrial function, reactive oxygen species (ROS) production, mitophagy, and lysosomal function were assessed in CLUH-knockout macrophages.
• A mouse model of colitis with CLUH knockdown was used to evaluate disease pathology.

Main Results:

• CLUH expression was reduced in active UC tissues and TLR-stimulated macrophages.
• CLUH negatively regulated the secretion of proinflammatory cytokines IL-6 and TNF-α.
• CLUH deficiency led to increased DRP1 availability, enhanced mitochondrial fission, and a dysfunctional mitochondrial pool.
• Absence of CLUH resulted in increased mitochondrial ROS production and impaired mitophagy and lysosomal function.
• CLUH knockdown exacerbated disease pathology in a mouse model of colitis.

Conclusions:

• CLUH plays a critical role in maintaining mitochondrial and lysosomal homeostasis in macrophages and intestinal mucosa.
• CLUH deficiency contributes to UC pathogenesis by promoting inflammation through impaired mitochondrial function.
• Targeting CLUH may represent a novel therapeutic approach for managing ulcerative colitis.