Figure 1.

Schematic illustration of the Ca²⁺and ATP flux across membranes. The ER is the major Ca²⁺ store. Ca²⁺ is transported against a steep concentration gradient into the lumen of the ER via the SERCA pump. Upon ligand stimulation, Ca²⁺ are released via the IP3R and RyR (here not shown) into the cytosol to activate Ca²⁺-dependent proteins. ATP import via AXER requires a Ca²⁺ gradient across the ER membrane and is inhibited in the presence of [Ca²⁺]_cyt > 500 nM. ATP, generated at the inner mitochondrial membrane by oxidative phosphorylation (ATP^∗∗), is preferentially transported into the ER. In the presence of high [Ca²⁺]_cyt, transport of ATP (ATP^∗) into the ER is discussed to be mediated by a yet unknown transporter. Misfolded proteins in the ER lead to ER-stress, which stimulates Ca²⁺ transfer from the ER to mitochondria. It is not clear whether Ca²⁺ uptake in mitochondria is coupled to ATP release. The refilling of intracellular Ca²⁺ stores by extracellular Ca²⁺ occurs via SOCE by close apposition of the transmembrane proteins STIM and ORAI. Close apposition of the mitochondrial and ER membrane occurs at MAM sites, in which high [Ca²⁺] prevail, a prerequisite for Ca²⁺ uptake into mitochondria. Further details are addressed in the text. AXER, ATP/ADP exchanger in the ER membrane; ER, endoplasmic reticulum; IP3R, inositol 1,4,5-trisphosphate receptor; MAM, mitochondria-associated ER-membrane; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase; SOCE, store-operated Ca²⁺ entry.