TY  - JOUR
AU  - Hoffmann, Christian
AU  - Nagao, Takahiro
AU  - Tsunoyama, Taka A
AU  - Tromm, Johannes Vincent
AU  - Logan, Chinyere
AU  - Nakamura, Koki
AU  - Wang, Han
AU  - Bianchi, Frans
AU  - van den Bogaart, Geert
AU  - Kusumi, Akihiro
AU  - Hirabayashi, Yusuke
AU  - Milovanovic, Dragomir
TI  - Membrane-protein-mediated phase separation orchestrates organelle contact sites.
JO  - Molecular cell
VL  - 86
IS  - 1
SN  - 1097-2765
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2026-00055
SP  - 135 - 149.e9
PY  - 2026
AB  - Mitochondria and the endoplasmic reticulum (ER) contain large areas that are in close proximity. Yet the mechanism of how these inter-organellar adhesions are formed remains elusive. Tight functional connections, termed 'membrane contact sites,' assemble at these areas and are essential for exchanging metabolites and lipids between the organelles. Recently, the ER-resident protein PDZ domain-containing protein 8 (PDZD8) was identified as a tether between the ER and mitochondria or late endosomes/lysosomes. Here, we show that PDZD8 can undergo phase separation via its intrinsically disordered region (IDR). Endogenously labeled PDZD8 forms condensates on membranes both in vitro and in mammalian cells. Electron microscopy analyses indicate that the expression of full-length PDZD8 rescues the decrease in inter-organelle contacts in PDZD8 knockout cells but not PDZD8 lacking its IDR. Together, this study identifies that PDZD8 condensates at the lipid interfaces act as an adhesive framework that stitches together the neighboring organelles and supports the structural and functional integrity of inter-organelle communication.
KW  - Humans
KW  - Endoplasmic Reticulum: metabolism
KW  - Endoplasmic Reticulum: ultrastructure
KW  - Endoplasmic Reticulum: genetics
KW  - Mitochondria: metabolism
KW  - Mitochondria: ultrastructure
KW  - Mitochondria: genetics
KW  - Membrane Proteins: metabolism
KW  - Membrane Proteins: genetics
KW  - Membrane Proteins: chemistry
KW  - HeLa Cells
KW  - HEK293 Cells
KW  - Animals
KW  - Intrinsically Disordered Proteins: metabolism
KW  - Intrinsically Disordered Proteins: genetics
KW  - Biomolecular Condensates: metabolism
KW  - Phase Separation
KW  - PDZD8 (Other)
KW  - biomolecular condensates (Other)
KW  - endoplasmic reticulum (Other)
KW  - liquid-liquid phase separation (Other)
KW  - membrane contact sites (Other)
KW  - mitochondria (Other)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Intrinsically Disordered Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41512824
DO  - DOI:10.1016/j.molcel.2025.12.006
UR  - https://pub.dzne.de/record/283176
ER  -