An inter-organelle contact between endosomal GLP-1R, ER VAP-B, and the mitochondrial AKAP SPHKAP triggers PKA-dependent MIC19 phosphorylation and β-cell mitochondrial remodelling

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing its turnover and improving its quality control. While the GLP-1R is well known to stimulate cAMP production leading to activation of Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) signalling, there is a lack of understanding of the molecular mechanisms linking GLP-1RA-induced signalling with mitochondrial remodelling and improved mitochondrial function. Here we present a dataset that demonstrates that, following GLP-1RA stimulation in pancreatic β-cells, the GLP-1R interacts with endoplasmic reticulum (ER) membrane contact site (MCS) organising factor VAP-B from an endocytic location to engage SPHKAP, an A-kinase anchoring protein (AKAP) associated with type 2 diabetes (T2D) and adiposity in genome-wide association studies (GWAS), to trigger a pool of mitochondrially localised PKA signalling that phosphorylates the mitochondrial contact site and cristae organizing system (MICOS) complex component MIC19, enabling GLP-1RA-induced mitochondrial remodelling and optimal β-cell function.