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Austin, G.* ; Oqua, A.I.* ; El Eid, L.* ; Zhu, M.* ; Manchanda, Y.* ; Peres, P.* ; Coyle, H.* ; Poliakova, Y.* ; Balkhiyarova, Z.* ; Bouzakri, K.* ; Montoya, A.* ; Withers, D.J.* ; Solimena, M. ; Jones, B.* ; Millership, S.J.* ; Burgold, S.* ; Gaboriau, D.C.A.* ; Majorovits, E.* ; Garlick, E.* ; do R B F Lima, M.A.* ; Prokopenko, I.* ; Nixon-Abell, J.* ; Müller, A. ; Tomas, A.*

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

Nat. Commun. 16:11010 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 11010 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Pancreatic Islet Research (IPI)