ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism
IP<sub>3</sub> receptor (IP<sub>3</sub>R)-mediated Ca<sup>2+</sup> transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca<sup>2+</sup> uptake and oxidative metabolism and is linked to different pathologies, including Parkinson's disease (PD). The dependence of Ca<sup>2+</sup> transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca<sup>2+</sup> indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca<sup>2+</sup> transfer and mitochondrial oxidative metabolism due to enrichment of IP<sub>3</sub>R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca<sup>2+</sup> uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca<sup>2+</sup> uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca<sup>2+</sup> flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.
Authors
- Carlos Matute (ORCID: https://orcid.org/0000-0001-8672-711X)
- Luigia Grazia Fresu (ORCID: https://orcid.org/0000-0002-8605-9040)
- Maria Talmon (ORCID: https://orcid.org/0000-0002-3914-5034)
- Claudio Casali (ORCID: https://orcid.org/0000-0001-8002-8262)
- Marisa Brini (ORCID: https://orcid.org/0000-0001-5141-0243)
- Mariagrazia Grilli (ORCID: https://orcid.org/0000-0001-9165-5827)
- Armando A. Genazzani (ORCID: https://orcid.org/0000-0003-1923-7430)
- Giulia Dematteis (ORCID: https://orcid.org/0000-0002-6317-3182)
- Marco Biggiogera (ORCID: https://orcid.org/0000-0003-3834-6712)
- Danielius Umbrasas (ORCID: https://orcid.org/0000-0001-6669-0575)
- Katsuhiko Mikoshiba (ORCID: https://orcid.org/0000-0002-3487-6970)
- Aistė Jekabsone (ORCID: https://orcid.org/0000-0003-1527-6221)
- Fabio Cavaliere (ORCID: https://orcid.org/0000-0003-2003-522X)
- Emanuela Pessolano (ORCID: https://orcid.org/0000-0003-1040-7288)
- Tito Calí (ORCID: https://orcid.org/0000-0002-8901-1659)
- Laura Tapella (ORCID: https://orcid.org/0000-0002-8159-1628)
- Carla Distasi (ORCID: https://orcid.org/0000-0001-8815-3252)
- Graham Ladds (ORCID: https://orcid.org/0000-0001-7320-9612)
- Gabriela Chrostek (ORCID: https://orcid.org/0000-0002-5235-1561)
- Paula Ramos‐Gonzalez
- Nicoletta Filigheddu (ORCID: https://orcid.org/0000-0002-3848-611X)
- Simone Reano (ORCID: https://orcid.org/0000-0002-5059-3620)
- Riccardo Miggiano (ORCID: https://orcid.org/0000-0002-2159-3314)
- Elisa Tonelli (ORCID: https://orcid.org/0009-0000-1868-6707)
- Dmitry Lim (ORCID: https://orcid.org/0000-0002-4316-2654)
- Gabrielė Kulkovienė (ORCID: https://orcid.org/0000-0003-1883-070X)
- Justyna Malecka (ORCID: https://orcid.org/0009-0002-1950-3364)
- Adele Ariotti
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Lithuanian University of Health Sciences (LT)
- University of Padua (IT)
- University of the Basque Country (ES)
- University of Cambridge (GB)
- University of Pavia (IT)
- ShanghaiTech University (CN)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Achucarro Basque Center for Neuroscience (ES)
- University of Turin (IT)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-10-10
- DOI
- https://doi.org/10.1038/s42003-024-06933-9
- Citations
- 43
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 10.05
Funders
- European Molecular Biology Organization
- Fondazione CRT
- Royal Society
- Eusko Jaurlaritza
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Università degli Studi di Pavia
- Università degli Studi del Piemonte Orientale
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council