ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism

G. Dematteis, LAURA PAOLA FERILDE TAPELLA, C. Casali, MARIA TALMON, E. Tonelli, S. Reano, A. Ariotti, E. Pessolano, J. Malecka, G. Chrostek, G. Kulkoviene, D. Umbrasas, Carla DISTASI, Mariagrazia GRILLI, G. Ladds, Nicoletta FILIGHEDDU, Luigia Grazia FRESU, K. Mikoshiba, C. Matute, P. Ramos-GonzalezA. Jekabsone, T. Cali, M. Brini, M. Biggiogera, F. Cavaliere, RICCARDO MIGGIANO, A. A. Genazzani, DMITRY LIM

Research output: Contribution to journalArticlepeer-review

Abstract

P3 receptor (IP3R)-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 IP3R 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.
Original languageEnglish
Number of pages15
JournalCommunications Biology
Volume7
Issue number1
DOIs
Publication statusPublished - 2024

Keywords

  • Endoplasmic reticulum
  • Energy metabolism

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