| Title: |
GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function |
| Authors: |
Austin, Gregory; Oqua, Affiong I.; El Eid, Liliane; Zhu, Mingli; Manchanda, Yusman; Peres, Priyanka; Coyle, Helena; Poliakova, Yelyzaveta; Bouzakri, Karim; Montoya, Alex; Withers, Dominic J.; Solimena, Michele; Jones, Ben; Millership, Steven J.; Burgold, Steffen; Gaboriau, David C.A.; Majorovits, Endre; Garlick, Evelyn; Lima, Maria; Prokopenko, Inga; Tomas, Alejandra |
| Contributors: |
Austin, Gregory; Oqua, Affiong I.; El Eid, Liliane; Zhu, Mingli; Manchanda, Yusman; Peres, Priyanka; Coyle, Helena; Poliakova, Yelyzaveta; Bouzakri, Karim; Montoya, Alex; Withers, Dominic J.; Solimena, Michele; Jones, Ben; Millership, Steven J.; Burgold, Steffen; Gaboriau, David C.A.; Majorovits, Endre; Garlick, Evelyn; Lima, Maria; Prokopenko, Inga; Tomas, Alejandra |
| Publication Year: |
2025 |
| Collection: |
Georg-August-Universität Göttingen: GoeScholar |
| Description: |
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. |
| Document Type: |
report |
| Language: |
unknown |
| DOI: |
10.1101/2024.04.28.591531 |
| Availability: |
https://resolver.sub.uni-goettingen.de/purl?gro-2/150907; https://doi.org/10.1101/2024.04.28.591531 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.D87F7D9 |
| Database: |
BASE |