Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering
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.
Authors
- Mohammadreza Paraan (ORCID: https://orcid.org/0000-0002-8402-0134)
- Jennifer Lippincott‐Schwartz (ORCID: https://orcid.org/0000-0002-8601-3501)
- Franck Polleux (ORCID: https://orcid.org/0000-0003-4313-0481)
- Saeko Aoyama-Ishiwatari (ORCID: https://orcid.org/0009-0001-6439-8922)
- Makoto Nakakido (ORCID: https://orcid.org/0000-0003-0328-9914)
- Yusuke Kishi (ORCID: https://orcid.org/0000-0003-2846-5400)
- Bridget Carragher (ORCID: https://orcid.org/0000-0002-0624-5020)
- Jake Johnston (ORCID: https://orcid.org/0000-0003-3060-7738)
- Yudan Du
- Yusuke Hirabayashi (ORCID: https://orcid.org/0000-0003-3950-6781)
- Hidetaka Kosako (ORCID: https://orcid.org/0000-0003-3228-6368)
- Koki Nakamura (ORCID: https://orcid.org/0000-0003-4885-4526)
- Hyun‐Woo Rhee (ORCID: https://orcid.org/0000-0002-3817-3455)
- Chulhwan Kwak (ORCID: https://orcid.org/0000-0003-0041-2681)
- Yukiko Gotoh (ORCID: https://orcid.org/0000-0001-9367-6648)
- Kouhei Tsumoto (ORCID: https://orcid.org/0000-0001-7643-5164)
- Masafumi Tsuboi (ORCID: https://orcid.org/0009-0001-2586-2200)
- Shogo Suga (ORCID: https://orcid.org/0009-0006-3424-0653)
- Christopher J. Obara (ORCID: https://orcid.org/0000-0003-1028-6076)
- Yui Sakurai-Saito
- Takahiro Nagao (ORCID: https://orcid.org/0009-0006-0541-9427)
- Jeong Kon Seo
- C.S. Potter
Institutions
- Howard Hughes Medical Institute (US)
- Seoul National University (KR)
- Janelia Research Campus (US)
- Columbia University Irving Medical Center (US)
- New York Structural Biology Center (US)
- Quantitative BioSciences (US)
- Chan Zuckerberg Initiative (United States) (US)
- Stanford Medicine (US)
- Ulsan National Institute of Science and Technology (KR)
- The University of Tokyo (JP)
- Tokushima University (JP)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1038/s41467-025-58538-3
- Citations
- 21
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 16.93
Funders
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- Secom Science and Technology Foundation
- University of Tokyo
- University of Tokushima
- Hokkaido University
- National Institutes of Health
- Japan Society for the Promotion of Science
- National Institute of Neurological Disorders and Stroke