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

Giulia Dematteis; Laura Tapella; Claudio Casali; Maria Talmon; Elisa Tonelli; Simone Reano; Adele Ariotti; Emanuela Pessolano; Justyna Malecka; Gabriela Chrostek; Gabrielė Kulkovienė; Danielius Umbrasas; Carla Distasi; Mariagrazia Grilli; Graham Ladds; Nicoletta Filigheddu; Luigia Grazia Fresu; Katsuhiko Mikoshiba; Carlos Matute; Paula Ramos‐Gonzalez; Aistė Jekabsone; Tito Calí; Marisa Brini; Marco Biggiogera; Fabio Cavaliere; Riccardo Miggiano; Armando A. Genazzani; Dmitry Lim

doi:10.1038/s42003-024-06933-9

Cell BiologyCommunications BiologyOct 10, 2024

Peer-reviewed journal article

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

Giulia Dematteis iD, Laura Tapella iD, Claudio Casali iD, Maria Talmon iD, Elisa Tonelli iD, Simone Reano iD, Adele Ariotti, Emanuela Pessolano iD, Justyna Malecka iD, Gabriela Chrostek iD, Gabrielė Kulkovienė iD, Danielius Umbrasas iD, Carla Distasi iD, Mariagrazia Grilli iD, Graham Ladds iD, Nicoletta Filigheddu iD, Luigia Grazia Fresu iD, Katsuhiko Mikoshiba iD, Carlos Matute iD, Paula Ramos‐Gonzalez iD, Aistė Jekabsone iD, Tito Calí iD, Marisa Brini iD, Marco Biggiogera iD, Fabio Cavaliere iD, , Dmitry Lim iD

Abstract

IP3 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 Parkinsons 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. 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.

PDF DOI