| Title: | GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function |
| Journal: | Nature Communications |
| Published: | 10 Dec 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41372122/ |
| DOI: | https://doi.org/10.1038/s41467-025-66115-x |
Publication 17245
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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.</p>
18 Keywords
- A Kinase Anchor Proteins
- Animals
- Cell Line
- Cyclic AMP-Dependent Protein Kinases
- Diabetes Mellitus, Type 2
- Endoplasmic Reticulum
- Endosomes
- Glucagon-Like Peptide-1 Receptor
- Humans
- Insulin-Secreting Cells
- Male
- Mice
- Mice, Inbred C57BL
- Mitochondria
- Mitochondria Associated Membranes
- Rats
- Signal Transduction
- Vesicular Transport Proteins
24 Authors
- Gregory Austin
- Affiong I. Oqua
- Liliane El Eid
- Mingli Zhu
- Yusman Manchanda
- Priyanka Peres
- Helena Coyle
- Yelyzaveta Poliakova
- Zhanna Balkhiyarova
- Karim Bouzakri
- Alex Montoya
- Dominic J. Withers
- Michele Solimena
- Ben Jones
- Steven J. Millership
- Steffen Burgold
- David C. A. Gaboriau
- Endre Majorovits
- Evelyn Garlick
- Maria Augusta do R. B. F. Lima
- Inga Prokopenko
- Jonathon Nixon-Abell
- Andreas Müller
- Alejandra Tomas
1 Application
| Application ID | Title |
|---|---|
| 35327 | Dissecting genetic relationships between type 2 diabetes, depression, and related phenotypes |
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