Three's company: Membrane waltz among organelles

The study of membrane contact sites (MCS) has profoundly transformed our understanding of inter-organelle communication. These sites, where the membranes of two organelles are closely apposed, facilitate the transfer of small molecules such as lipids and ions. They are especially crucial for the maintenance of the structure and function of organelles like mitochondria and lipid droplets, which are largely excluded from vesicular trafficking. The significant advancements in imaging techniques, and molecular and cell biology research have shown that MCS are more complex than what originally thought and can involve more than two organelles. This has revealed the intricate nature and critical importance of these subcellular connections. Here, we provide an overview of newly described three-way inter-organelles associations, and the proteins involved in these MCS. We highlight the roles these contacts play in key cellular processes such as lipid droplet biogenesis and mitochondrial division. Additionally, we discuss the latest advances in super-resolution imaging that enable the study of these complex three-way interactions. Ongoing research, driven by technological innovations, promises to uncover further insights into their roles in fundamental cellular processes and their implications for health and disease.