1. ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism.
- Author
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Dematteis, Giulia, Tapella, Laura, Casali, Claudio, Talmon, Maria, Tonelli, Elisa, Reano, Simone, Ariotti, Adele, Pessolano, Emanuela, Malecka, Justyna, Chrostek, Gabriela, Kulkovienė, Gabrielė, Umbrasas, Danielius, Distasi, Carla, Grilli, Mariagrazia, Ladds, Graham, Filigheddu, Nicoletta, Fresu, Luigia Grazia, Mikoshiba, Katsuhiko, Matute, Carlos, and Ramos-Gonzalez, Paula
- Abstract
IP
3 receptor (IP3 R)-mediated Ca2+ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca2+ uptake and oxidative metabolism and is linked to different pathologies, including Parkinson’s disease (PD). The dependence of Ca2+ 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 Ca2+ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca2+ transfer and mitochondrial oxidative metabolism due to enrichment of IP3 R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca2+ uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca2+ uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca2+ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.The distance-dependence analysis of ER-mitochondria Ca2+ transfer suggests that a distance of ∼20 nm between the organelles ensures maximal efficiency of mitochondrial Ca2+ uptake and OXPHOS and rescues Ca2+ uptake in Parkinson’s disease mitochondria. [ABSTRACT FROM AUTHOR]- Published
- 2024
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