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

Area of Science:

• Molecular biology
• Cell biology
• Endocrinology

Background:

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

Purpose of the Study:

• To elucidate the molecular pathways linking GLP-1R signaling to mitochondrial and beta-cell functional adaptation.
• To investigate the role of specific protein interactions at ER-mitochondria contact sites in mediating these effects.

Main Methods:

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

Main Results:

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

Conclusions:

• A novel signaling complex at ERMCSs mediates GLP-1R-induced mitochondrial adaptation and beta-cell protection.
• This pathway involving VAPB, SPHKAP, and PKA is critical for beta-cell function and resilience in metabolic stress.
• Findings offer new insights into T2D pathogenesis and potential therapeutic targets.