GLP-1 receptor and Mitochondria-ER Contact Sites: an emerging mechanism of metabolic regulation

The uncoupling of Mitochondria-ER Contact Sites (MERCS) represents a hallmark of metabolic dysfunction in obesity and type 2 diabetes. These are dynamic interfaces that play essential roles in coordinating ion signaling and lipid exchange to maintain cellular homeostasis. Persistent organelle stress in chronic disease impairs these pathways, driving systemic hormone resistance and metabolic failure. A paradigm shifts in glucagon-like peptide-1 receptor (GLP-1R) signaling from diffuse events to spatiotemporally organized signalosomes offer insightful mechanisms into these conditions. The localization of internalized GLP-1Rs at the Mitochondria-ER interface supports a contactomics framework for understanding bioenergetic restoration. Stabilizing inter-organellar connectivity represents a novel frontier for next-generation metabolic therapies.