Journal Article

DZNE-2026-00055

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Membrane-protein-mediated phase separation orchestrates organelle contact sites.

Hoffmann, C. (First author)DZNE* ; Nagao, T. ; Tsunoyama, T. A. ; Tromm, J. V.DZNE* ; Logan, C.DZNE* ; Nakamura, K. ; Wang, H.Extern* ; Bianchi, F. ; van den Bogaart, G. ; Kusumi, A. ; Hirabayashi, Y. ; Milovanovic, D. (Last author)DZNE*

2026
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: doi:10.1016/j.molcel.2025.12.006

Abstract: 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.

Keyword(s): Humans (MeSH) ; Endoplasmic Reticulum: metabolism (MeSH) ; Endoplasmic Reticulum: ultrastructure (MeSH) ; Endoplasmic Reticulum: genetics (MeSH) ; Mitochondria: metabolism (MeSH) ; Mitochondria: ultrastructure (MeSH) ; Mitochondria: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Membrane Proteins: genetics (MeSH) ; Membrane Proteins: chemistry (MeSH) ; HeLa Cells (MeSH) ; HEK293 Cells (MeSH) ; Animals (MeSH) ; Intrinsically Disordered Proteins: metabolism (MeSH) ; Intrinsically Disordered Proteins: genetics (MeSH) ; Biomolecular Condensates: metabolism (MeSH) ; Phase Separation (MeSH) ; PDZD8 ; biomolecular condensates ; endoplasmic reticulum ; liquid-liquid phase separation ; membrane contact sites ; mitochondria ; Membrane Proteins ; Intrinsically Disordered Proteins

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Contributing Institute(s):

1. Molecular Neuroscience (AG Milovanovic (Berlin))

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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