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

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, Kouhei Tsumoto, Yusuke Kishi, Yukiko Gotoh, Chulhwan Kwak, Hyun-Woo Rhee, Jeong Kon Seo, Hidetaka Kosako, Clint Potter, Bridget Carragher, Jennifer Lippincott-Schwartz, Franck Polleux and Yusuke Hirabayashi ()
Additional contact information
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
Christopher J. Obara: Howard Hughes Medical Institute
Yui Sakurai-Saito: The University of Tokyo
Jake Johnston: New York Structural Biology 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
Kouhei Tsumoto: The University of Tokyo
Yusuke Kishi: The University of Tokyo
Yukiko Gotoh: The University of Tokyo
Chulhwan Kwak: Seoul National University
Hyun-Woo Rhee: Seoul National University
Jeong Kon Seo: Ulsan National Institute of Science and Technology (UNIST)
Hidetaka Kosako: Tokushima University
Clint Potter: New York Structural Biology Center
Bridget Carragher: New York Structural Biology Center
Jennifer Lippincott-Schwartz: Howard Hughes Medical Institute
Franck Polleux: Columbia University Medical Center
Yusuke Hirabayashi: The University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58538-3

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