The endoplasmic reticulum (ER) acts as a central coordinator of inter-organelle communication by establishing membrane contact sites (MCSs) with diverse cellular compartments, including mitochondria, peroxisomes, the plasma membrane, lipid droplets, stress granules, and ribosomes. Among these, ER–mitochondria contact sites, also known as mitochondria-associated membranes (MAMs) have emerged as critical hubs for the regulation of autophagy, metabolic signaling, reactive oxygen species (ROS) production, and programmed cell death.
Our recent work has identified a large multimeric protein complex that specifically assembles at MAMs. This complex comprises ER-resident chaperones, ER-phagy receptors, and mitochondrial MAM-associated proteins, and it orchestrates the selective autophagic degradation of ER–mitochondria contact sites. We term this process contact-phagy, a specialized form of selective autophagy that enables dynamic remodeling of MAM architecture. Through this mechanism, cells can fine-tune inter-organelle communication and preserve homeostasis under both physiological and stress conditions.