ArticleNature communications2025
GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- GLP-1 Receptor Agonists as Molecular Relievers of Lipotoxic Stress: From Pancreatic Beta-Cell Cholesterol Efflux to Systemic and Tissue-Specific Metabolic Protection.International journal of molecular sciences · 2026Review
- Islet ultrastructure: past achievements and future directions.Diabetologia · 2026Review
- Advanced imaging of membrane contact sites.Nature cell biology · 2026Review
- Tirzepatide attenuates doxorubicin-induced cardiotoxicity via mitochondrial function improvement.Translational cancer research · 2026Article
- Modelling G protein-biased agonism using GLP-1 receptor C-terminal mutations.Molecular metabolism · 2026Article
- In vivo functional profiling and structural characterization of the humanScience advances · 2026Article
- Signaling architecture of the glucagon-like peptide-1 receptor.The Journal of clinical investigation · 2026Review
- Long-chain saturated free fatty acids induce pancreatic β-cell lipotoxic stress via HFrontiers in endocrinology · 2026Article
- GLP-1 receptor and Mitochondria-ER Contact Sites: an emerging mechanism of metabolic regulation.Frontiers in physiology · 2026Review
- Spatially diffuse cAMP signalling with oppositely biased GLP-1 receptor agonists in β-cells despite differences in receptor localisation.Molecular metabolism · 2026Article
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24 authors.
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Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic β-cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and β-cell functional adaptation. Here, we present a comprehensive study in β-cell lines and primary islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic reticulum (ER) membrane contact site (MCS) tether VAPB at ER-mitochondria MCSs (ERMCSs), where active GLP-1R engages with SPHKAP, an A-kinase anchoring protein (AKAP) previously linked to T2D and adiposity risk in genome-wide association studies (GWAS). The inter-organelle complex formed by endosomal GLP-1R, ER VAPB and SPHKAP triggers a pool of ERMCS-localised cAMP/PKA signalling via the formation of a PKA-RIα biomolecular condensate which leads to changes in mitochondrial contact site and cristae organising system (MICOS) complex phosphorylation, mitochondrial remodelling, and β-cell functional adaptation, with important consequences for the regulation of β-cell insulin secretion and survival to stress.
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