An inter-organelle contact between endosomal GLP-1R, ER VAP-B, and the mitochondrial AKAP SPHKAP triggers PKA-dependent MIC19 phosphorylation and β-cell mitochondrial remodelling

Austin, G.; ElEid, L.; Oqua, A. I.; Manchanda, Y.; Poliakova, Y.; Bouzakri, K.; Montoya, A.; Withers, D. J.; Jones, B.; Millership, S. J.; Prokopenko, I.; Tomas, A.

doi:10.1101/2024.04.28.591531

bioRxiv · 10.1101/2024.04.28.591531

An inter-organelle contact between endosomal GLP-1R, ER VAP-B, and the mitochondrial AKAP SPHKAP triggers PKA-dependent MIC19 phosphorylation and β-cell mitochondrial remodelling

Austin, G.·ElEid, L.·Oqua, A. I.·Manchanda, Y.·Poliakova, Y.·Bouzakri, K.·Montoya, A.·Withers, D. J.·Jones, B.·Millership, S. J.·Prokopenko, I.·Tomas, A.

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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 {beta}-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 {beta}-cell functional adaptation. Here, we present a comprehensive study in {beta}-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-RI biomolecular condensate which leads to changes in mitochondrial contact site and cristae organising system (MICOS) complex phosphorylation, mitochondrial remodelling, and {beta}-cell functional adaptation, with important consequences for the regulation of {beta}-cell insulin secretion and survival to stress.

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Austin, G., ElEid, L., Oqua, A. I., Manchanda, Y., Poliakova, Y., Bouzakri, K., Montoya, A., Withers, D. J., Jones, B., Millership, S. J., Prokopenko, I., Tomas, A.. 2024-04-30. An inter-organelle contact between endosomal GLP-1R, ER VAP-B, and the mitochondrial AKAP SPHKAP triggers PKA-dependent MIC19 phosphorylation and β-cell mitochondrial remodelling. https://doi.org/10.1101/2024.04.28.591531

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