2025年新着論文 13　細胞情報学分野から論文が発表されました

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

Nat Commun. 2025 Apr 17;16(1):3401. doi: 10.1038/s41467-025-58538-3.

Authors

Koki Nakamura^#¹, Saeko Aoyama-Ishiwatari^#¹, Takahiro Nagao^#¹, Mohammadreza Paaran^2 3, Christopher J Obara⁴, Yui Sakurai-Saito⁵, Jake Johnston^2 6, Yudan Du¹, Shogo Suga¹, Masafumi Tsuboi¹, Makoto Nakakido^1 5, Kouhei Tsumoto^{1 5 7}, Yusuke Kishi^8 9, Yukiko Gotoh⁸, Chulhwan Kwak^10 11, Hyun-Woo Rhee¹², Jeong Kon Seo^13 14, Hidetaka Kosako¹⁵, Clint Potter^2 3, Bridget Carragher^2 3, Jennifer Lippincott-Schwartz⁴, Franck Polleux^16 17, Yusuke Hirabayashi^18 19

Affiliations

¹ Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan.
² Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, 10028, USA.
³ Chan Zuckerberg Imaging Institute, Redwood City, CA, USA.
⁴ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, 20147, USA.
⁵ Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan.
⁶ Columbia University Medical Center, New York, NY, 10032, USA.
⁷ Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
⁸ Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan.
⁹ Laboratory of Molecular Neurobiology, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, 113-0032, Japan.
¹⁰ Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea.
¹¹ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94304, USA.
¹² School of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
¹³ Graduate School of Semiconductor Materials and Devices Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
¹⁴ UNIST Central Research Facilities (UCRF), Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Korea.
¹⁵ Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, 770-8503, Japan.
¹⁶ Department of Neuroscience, Columbia University Medical Center, New York, NY, 10032, USA.
¹⁷ Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY, 10027, USA.
¹⁸ Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan. hirabayashi@chembio.t.u-tokyo.ac.jp.
¹⁹ Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan. hirabayashi@chembio.t.u-tokyo.ac.jp.

^# Contributed equally.

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.

Conflict of interest statement

Competing interests: The authors declare no competing interests.

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