Gregory L. Austin, Affiong I Oqua, Liliane El Eid, Meng 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 Rego Barros Fernandes Lima, Inga Prokopenko, Jonathon Nixon‐Abell, Andreas Müller, Alejandra Tomás
Our data demonstrate that dysregulated MAMs constitute a mechanistic link between saturated-FFA-induced lipotoxic stress and β-cell failure in T2D. Targeting MAM remodeling or the upstream H2O2 signal may represent a novel therapeutic avenue to preserve β-cell function under lipotoxic conditions.
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.