GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function

Area of Science:

• Cell Biology
• Endocrinology
• Metabolic Diseases

Background:

• Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve mitochondrial health and beta-cell function, vital for type 2 diabetes (T2D) management.
• The precise molecular mechanisms linking GLP-1R signaling to mitochondrial adaptation and beta-cell function remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which GLP-1R agonists regulate mitochondrial function and beta-cell adaptation.
• To identify novel signaling pathways involved in GLP-1R-mediated effects on pancreatic beta-cells.

Main Methods:

• Utilized beta-cell lines and primary islets for comprehensive analysis.
• Investigated the association of GLP-1R-positive endosomes with ER-mitochondria contact sites (ERMCSs).
• Examined the role of VAPB, SPHKAP, and PKA signaling in mediating GLP-1RA effects.

Main Results:

• GLP-1RA stimulation leads to GLP-1R endosome association with ER VAPB at ERMCSs.
• An ERMCS-localized complex involving GLP-1R, VAPB, and SPHKAP triggers cAMP/PKA signaling.
• This signaling cascade results in MICOS complex phosphorylation, mitochondrial remodeling, and enhanced beta-cell function and stress survival.

Conclusions:

• A novel signaling pathway at ER-mitochondria contact sites mediates GLP-1RA effects on beta-cell mitochondrial health and function.
• This pathway involves the formation of a PKA-RIα biomolecular condensate, impacting mitochondrial structure and beta-cell resilience.
• Findings provide new insights into T2D pathogenesis and potential therapeutic targets for beta-cell protection.