Calcium at the Center of Cell Signaling: Interplay between Endoplasmic Reticulum, Mitochondria, and Lysosomes

Abstract

In recent years, rapid discoveries have been made relating to Ca²⁺ handling at specific organelles that have important implications for whole-cell Ca²⁺ homeostasis. In particular, the structures of the endoplasmic reticulum (ER) Ca²⁺ channels revealed by electron cryomicroscopy (cryo-EM), continuous updates on the structure, regulation, and role of the mitochondrial calcium uniporter (MCU) complex, and the analysis of lysosomal Ca²⁺ signaling are milestones on the route towards a deeper comprehension of the complexity of global Ca²⁺ signaling. In this review we summarize recent discoveries on the regulation of interorganellar Ca²⁺ homeostasis and its role in pathophysiology.

FIGURE 1. Endoplasmic Reticulum (ER) Ca²⁺ store and ER-mitochondria contact sites

Following ligand bindingto a GPCR, subsequent activation of PLC triggers the production of InsP₃and DAG from PIP₂. InsP₃ binds to InsP₃Rs at the ER membrane, thus Ca²⁺ is released from the ER into the cytosol. Conversely, Ca²⁺ is withdrawn into the ER by SERCA activity. The proximity between ER and mitochondria ensures the formation of high [Ca²⁺] microdomains, allowing mitochondria to rapidly take up Ca²⁺. VDACs are responsible for the rapid transfer of Ca²⁺ through the OMM, then accumulation of Ca²⁺ into the mitochondrial matrix occurs via MCU. A number of regulatory proteins contribute to the regulation ofER-mitochondria contact sites.+ . Red dots indicate Ca²⁺. GPCR: G-protein coupled receptor PLC: phospholipase C PIP₂: phosphatidylinositol 4,5-bisphosphate InsP₃: inositol 1,4,5-trisphosphate DAG: diacylglycerol InsP₃Rs: inositol 1,4,5-trisphosphate receptors ER: endoplasmic reticulum SERCA: sarco(endo)plasmic reticulum calcium ATPase VDACs: voltage-dependent anion channels OMM: outer mitochondrial membrane

FIGURE 2. Schematic representation of store operated Ca²⁺ entry (SOCE)

Immediately following a decrease in ER [Ca²⁺] (left hand side) STIM1 form multimers. STIM1 multimers translocate to the plasma membrane-ER contact sites where they recruit ORAI1 channels, leading to Ca²⁺ entry from the extracellular space. In resting conditions (right hand side), when the ER [Ca²⁺] is high, Ca²⁺ is bound to the STIM1 EF-hand domain. In this conformation of STIM1 is not able to form multimers, and thus SOCE is inactivated. Red dots indicate Ca²⁺. ER: endoplasmic reticulum SOCE: store-operated Ca²⁺ entry

FIGURE 3. Schematic representation of the MCU complex

Mitochondrial calcium uptake is controlled by a multiprotein complex composed of the pore forming subunits MCU and MCUb together with MICU1, MICU2 and EMRE. In resting conditions (left hand side), MICU1/MICU2 heterodimers act as the MCU gatekeeper, due to the inhibitory effect of MICU2. Once Ca²⁺ signaling is activated (right hand side), the increase in cytosolic [Ca²⁺] induces a conformational change in the dimer that releases MICU2-dependent inhibition. At the same time, MICU1 acts as a cooperative activator of the channel, and thus stimulates the channel activity. Red dots indicate Ca²⁺.

FIGURE 4. Trigger hypothesis of NAADP-induced Ca²⁺ release

NAADP evokes a Ca²⁺-induced Ca²⁺ release response from the ER. NAADP acts at TPCs on lysosome-related Ca²⁺ stores to elicit a local Ca²⁺ release (middle). The increase in [Ca²⁺] at the endolysosome-ER interface sensitizes the InsP₃R, thus evoking a global Ca²⁺ wave (right hand side). Red dots indicate Ca²⁺. ER: endoplasmic reticulum NAADP: nicotinic acid dinucleotide phosphate TPCs: Two-Pore channels InsP₃R: inositol 1,4,5-trisphosphate receptor

FIGURE 5. Ion channels and transporters in the endolysosome

TRPML and TPC channels are involved in the release of Ca²⁺ from the endolysosome. Conversely, the activity of the vacuolar (V)-type H⁺-ATPase provides the energy required for Ca²⁺ entry into the lysosome by H⁺/Ca²⁺ exchanger. TRPML: Mucolipin family of Transient Receptor Potential TPC: Two-Pore channel