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ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism
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Journal Article
ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism
2024
Overview
IP
3
receptor (IP
3
R)-mediated Ca
2+
transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca
2+
uptake and oxidative metabolism and is linked to different pathologies, including Parkinson’s disease (PD). The dependence of Ca
2+
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
2+
indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca
2+
transfer and mitochondrial oxidative metabolism due to enrichment of IP
3
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
2+
uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca
2+
uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca
2+
flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.
The distance-dependence analysis of ER-mitochondria Ca
2+
transfer suggests that a distance of ∼20 nm between the organelles ensures maximal efficiency of mitochondrial Ca
2+
uptake and OXPHOS and rescues Ca
2+
uptake in Parkinson’s disease mitochondria.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/100
/ 13/95
/ 14/19
/ 14/28
/ 14/34
/ 14/63
/ 96/109
/ 96/44
/ Biomedical and Life Sciences
