How the ER and Mitochondria Stick Together: A New Mechanism of Intracellular Architecture Formation by Liquid-Like Protein Assemblies

Inside cells, the endoplasmic reticulum (ER) and mitochondria come into remarkably close proximity, separated by just 10–30 nanometers, forming tightly adhesive and widely spread structures known as mitochondria–ER contact sites. These contact sites are essential for cellular homeostasis, including lipid transfer and calcium regulation. However, the driving force that allows these contacts to expand into broad and uniform surface areas has long remained unclear. In this study, the research team uncovered an unexpected mechanism in which the ER-resident protein PDZD8 acts like a liquid-like glue that brings the ER and mitochondria together. Using a combination of in vitro reconstitution, genome-edited knock-in cells, ultrafast single-molecule imaging, and electron microscopy, the researchers showed that PDZD8 undergoes liquid–liquid phase separation, forming soft condensates that spread between the two organelles and promote their adhesion through surface tension. By revealing a fundamental principle of intracellular structure formation, this work provides new insight into cellular organization and may contribute to understanding the molecular basis of disorders such as autism.

Papers

Journal: Molecular Cell

Title: Membrane-protein-mediated phase separation orchestrates organelle contact sites

Authors: Christian Hoffmann^#, Takahiro Nagao^#, Taka A. Tsunoyama, Johannes Vincent Tromm, Chinyere Logan, Koki Nakamura, Han Wang, Frans Bianchi, Geert van den Bogaart, Akihiro Kusumi, Yusuke Hirabayashi*, Dragomir Milovanovic*

  ^#These authors contributed equally to this work (alphabetical order)

  *Corresponding authors

DOI: 10.1016/j.molcel.2025.12.006