BIN1 and ALDH1B1 Deficiency in Colonic Smooth Muscle Drives Mitochondrial Dysfunction and Fibrosis in Slow-Transit...

Area of Science:

• Gastroenterology
• Cell Biology
• Molecular Medicine

Background:

• Slow-transit constipation (STC) is a severe motility disorder with poorly understood smooth muscle dysfunction.
• Identifying the molecular mechanisms in colonic smooth muscle is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of specific proteins in the smooth muscle dysfunction observed in slow-transit constipation.
• To identify novel therapeutic targets for restoring intestinal motility.

Main Methods:

• Spatial proteomics was employed on human colon samples.
• Functional assays were conducted on primary human colonic smooth muscle cells (HCoSMCs).
• Lentiviral knockdown was used to study the effects of BIN1 and ALDH1B1 reduction.

Main Results:

• Bridging Integrator 1 (BIN1) and Aldehyde Dehydrogenase 1B1 (ALDH1B1) were found to be significantly reduced in STC patients' smooth muscle.
• Knockdown of BIN1 or ALDH1B1 impaired muscle cell contractility, mitochondrial function, and increased oxidative stress.
• BIN1 deficiency led to apoptosis and fibrosis, while ALDH1B1 loss induced mitophagy and inflammation, converging on profibrotic pathways.

Conclusions:

• BIN1 and ALDH1B1 are key regulators of intestinal smooth muscle function and motility.
• Their reduction contributes to the pathogenesis of slow-transit constipation through distinct cellular mechanisms.
• BIN1 and ALDH1B1 represent promising therapeutic targets for treating STC and restoring intestinal motility.