# STIM1-containing contact sites promote direct calcium flux from the endoplasmic reticulum to mitochondria

## TL;DR

This study reveals that STIM1 helps transfer calcium directly from the endoplasmic reticulum to mitochondria, supporting mitochondrial function and energy production.

## Contribution

The study identifies a new role for STIM1 in direct ER-mitochondria calcium transfer, independent of its known function in store-operated calcium entry.

## Key findings

- STIM1 interacts with mitochondrial proteins GRP75 and PTPIP51 in ER-mitochondria contact sites.
- STIM1 deficiency increases contact sites but reduces functional calcium transfer to mitochondria.
- A specific STIM1 region (amino acids 551-611) is essential for GRP75 binding and calcium transfer.

## Abstract

STIM1 is a transmembrane protein localized in the endoplasmic reticulum (ER), where it acts as a calcium ion sensor, activating store-operated Ca2+ entry upon ER Ca2+ depletion. Via cellular calcium influx, STIM1 is thought to indirectly affect mitochondrial calcium content. Here we show that STIM1 also interacts with mitochondrial proteins such as PTPIP51 and GRP75, suggesting its presence in mitochondria-associated ER membranes (MAMs), which are specialized ER regions that facilitate ER-mitochondria communication. Lowering STIM1 expression disrupts ER-to-mitochondria Ca2+ transfer, reduces basal mitochondrial Ca2+ levels, impairs maximal mitochondrial respiration, and reduces ATP production. The STIM1-GRP75 interaction depends on STIM1’s Ca2+-sensing ability. ER Ca2+ depletion or the constitutive-open R429C mutation both reduce STIM1 binding to GRP75, suggesting that conformational changes in STIM1 play a role in this interaction. Deletion analysis revealed that the STIM1 (551-611) segment is crucial for GRP75 binding, as the peptide STIM1(551-611) binds GRP75, while STIM1(Δ551-611) shows reduced binding. These findings reveal a previously unrecognized role of STIM1 in direct inter-organelle communication.

STIM1 senses the calcium content of the ER lumen and forms plasma membrane contact sites when calcium levels are low. This study shows that STIM1 also interacts with mitochondrial proteins GRP75 and PTPIP51 in ER-mitochondria contact sites, which mediate the direct transfer of Ca2+ from ER to mitochondria.

STIM1 deficiency increases the number of ER-mitochondria contacts sites but reduces functional Ca2+ transfer to mitochondria.The interaction between STIM1 and GRP75 depends on STIM1’s conformation, with the closed form promoting binding.A specific STIM1 region (amino acids 551-611) is essential for GRP75 binding and proper ER-mitochondria Ca2+ transfer, independent of its role in store-operated calcium entry.

STIM1 deficiency increases the number of ER-mitochondria contacts sites but reduces functional Ca2+ transfer to mitochondria.

The interaction between STIM1 and GRP75 depends on STIM1’s conformation, with the closed form promoting binding.

A specific STIM1 region (amino acids 551-611) is essential for GRP75 binding and proper ER-mitochondria Ca2+ transfer, independent of its role in store-operated calcium entry.

STIM1 regulates ER-to-mitochondria Ca2+ transfer via its interaction with GRP75, maintaining mitochondrial homeostasis and contact site integrity.