Figure 4. Calcium (Ca²⁺) exchange at endoplasmic reticulum (ER) membrane contact sites (MCSs).

a | The ER lumen is the major Ca²⁺ store in the cell, with a Ca²⁺ concentration ([Ca²⁺]) of ~60–500 μM). In the extracellular space, [Ca²⁺] is high (~1mM) compared to the intracellular cytosol (~100nM). Newly formed endosomes have taken up Ca²⁺ from the extracellular space, so the luminal [Ca²⁺] is close to the same as that of the extracellular space (~1 mM). Luminal Ca²⁺ is then released so that early endosomes have [Ca²⁺] ~0.5 μM and late endosomes have [Ca²⁺] ~2.5 μM. The ER–endosome MCS is a site of dynamic Ca²⁺ crosstalk. Endosomes may be able to sequester Ca²⁺ released from the ER. The ER transfers Ca²⁺ to mitochondria, with peak mitochondrial Ca²⁺ concentrations reaching 100 μM. b | ER Ca²⁺ released from the ER through inositol-1,4,5- trisphosphate receptors (Ins(1,4,5)P₃Rs) provides a concentrated Ca²⁺ spike that can be taken up through the outer mitochondrial membrane (OMM) by VDACs (voltage dependent anion channels) and then through the inner mitochondrial membrane (IMM) by the mitochondrial Ca²⁺ uniporter (MCU) ion transporter into the mitochondrial matrix. The 75 kDa glucose-regulated protein (GRP75) functions as a chaperone, coupling Ins(1,4,5)P₃R to the VDACs. c | Endosomes are capable of releasing Ca²⁺ though transient receptor potential channels (TRPs) or two-pore channels (TPCs). ER Ca²⁺ released from ER via Ins(1,4,5)P₃Rs could be taken up into endosomes through unknown endosome Ca²⁺-uptake channels. Ca²⁺ release from endosomes can also stimulate Ca²⁺ release from the ER through Ins(1,4,5)P₃Rs and vice versa.