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Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering

Author

Listed:
  • Koki Nakamura

    (The University of Tokyo)

  • Saeko Aoyama-Ishiwatari

    (The University of Tokyo)

  • Takahiro Nagao

    (The University of Tokyo)

  • Mohammadreza Paaran

    (New York Structural Biology Center
    Chan Zuckerberg Imaging Institute)

  • Christopher J. Obara

    (Howard Hughes Medical Institute)

  • Yui Sakurai-Saito

    (The University of Tokyo)

  • Jake Johnston

    (New York Structural Biology Center
    Columbia University Medical Center)

  • Yudan Du

    (The University of Tokyo)

  • Shogo Suga

    (The University of Tokyo)

  • Masafumi Tsuboi

    (The University of Tokyo)

  • Makoto Nakakido

    (The University of Tokyo
    The University of Tokyo)

  • Kouhei Tsumoto

    (The University of Tokyo
    The University of Tokyo
    The University of Tokyo)

  • Yusuke Kishi

    (The University of Tokyo
    The University of Tokyo)

  • Yukiko Gotoh

    (The University of Tokyo)

  • Chulhwan Kwak

    (Seoul National University
    Stanford University School of Medicine)

  • Hyun-Woo Rhee

    (Seoul National University)

  • Jeong Kon Seo

    (Ulsan National Institute of Science and Technology (UNIST)
    Ulsan National Institute of Science and Technology (UNIST))

  • Hidetaka Kosako

    (Tokushima University)

  • Clint Potter

    (New York Structural Biology Center
    Chan Zuckerberg Imaging Institute)

  • Bridget Carragher

    (New York Structural Biology Center
    Chan Zuckerberg Imaging Institute)

  • Jennifer Lippincott-Schwartz

    (Howard Hughes Medical Institute)

  • Franck Polleux

    (Columbia University Medical Center
    Mortimer B. Zuckerman Mind Brain Behavior Institute)

  • Yusuke Hirabayashi

    (The University of Tokyo
    The University of Tokyo)

Abstract

Mitochondria-ER membrane contact sites (MERCS) represent a fundamental ultrastructural feature underlying unique biochemistry and physiology in eukaryotic cells. The ER protein PDZD8 is required for the formation of MERCS in many cell types, however, its tethering partner on the outer mitochondrial membrane (OMM) is currently unknown. Here we identify the OMM protein FKBP8 as the tethering partner of PDZD8 using a combination of unbiased proximity proteomics, CRISPR-Cas9 endogenous protein tagging, Cryo-electron tomography, and correlative light-electron microscopy. Single molecule tracking reveals highly dynamic diffusion properties of PDZD8 along the ER membrane with significant pauses and captures at MERCS. Overexpression of FKBP8 is sufficient to narrow the ER-OMM distance, whereas independent versus combined deletions of these two proteins demonstrate their interdependence for MERCS formation. Furthermore, PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner. Our results identify a novel ER-mitochondria tethering complex that regulates mitochondrial morphology in mammalian cells.

Suggested Citation

  • Koki Nakamura & Saeko Aoyama-Ishiwatari & Takahiro Nagao & Mohammadreza Paaran & Christopher J. Obara & Yui Sakurai-Saito & Jake Johnston & Yudan Du & Shogo Suga & Masafumi Tsuboi & Makoto Nakakido & , 2025. "Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58538-3
    DOI: 10.1038/s41467-025-58538-3
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