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IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake
Andras T Deak1, Sandra Blass1, Muhammad J Khan1
1The Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010-Graz, Austria.
Journal of Cell Science
|May 9, 2014
Summary
Mitochondria regulate store-operated calcium entry (SOCE) by influencing STIM1. Mitochondrial calcium uptake, via MCU or UCP2, is crucial for SOCE regulation and preventing its deactivation.
Area of Science:
- Cellular biology
- Mitochondrial function
- Calcium signaling
Background:
- Mitochondria play a role in cell signaling through calcium regulation.
- Store-operated calcium entry (SOCE) is a critical process involving calcium release from the endoplasmic reticulum (ER) and activation of plasma membrane calcium channels by STIM1.
- The precise mechanisms by which mitochondria modulate SOCE remain unclear.
Purpose of the Study:
- To investigate the direct role of mitochondrial calcium buffering in SOCE.
- To elucidate how mitochondrial calcium uptake proteins, MCU and UCP2, affect SOCE dynamics.
Main Methods:
- Utilized an shRNA approach to knock down key mitochondrial calcium uptake proteins (MCU, UCP2).
- Stimulated cells with an IP3-generating agonist to activate SOCE.
- Manipulated cytosolic calcium buffering and ER calcium levels using pharmacological inhibitors (SERCA inhibitors).
Main Results:
- Knockdown of MCU or UCP2 significantly slowed STIM1 oligomerization and impaired SOCE.
- STIM1 oligomerization was independent of mitochondrial calcium uptake when cytosolic buffering was enhanced or ER calcium was depleted.
- Mitochondrial calcium sequestration via MCU was essential for preventing the slow deactivation of SOCE.
Conclusions:
- Mitochondrial calcium uptake contributes to SOCE in a stimulus-dependent manner.
- Mitochondria influence SOCE likely by shaping local cytosolic calcium micro-domains.
- MCU-dependent mitochondrial calcium buffering is critical for SOCE regulation and timely deactivation.
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