Mitochondrial Ca²⁺ sequestration is an important physiological process that is linked to many different cellular responses such diverse as metabolic stimulation and energy deprivation or cell proliferation and cell death. This diversity of physiological consequences for a cell triggered by mitochondrial Ca²⁺ loads is controlled by the spatial and temporal patterns as well as by the intensity of mitochondrial Ca²⁺ signals. Mitochondrial Ca²⁺ uptake under physiological conditions is thought to be mainly accomplished by the so called mitochondrial Ca²⁺ uniporter (MCU) albeit alternative pathways such as a reversed mode of the mitochondrial 3Na⁺/ Ca²⁺-exchanger (NCX_mito) have been recently introduced, too. The MCU was characterized as a highly Ca²⁺ selective inward rectifying ion channel at the inner mitochondrial membrane with a quite low Ca²⁺ affinity. We have recently demonstrated that the novel uncoupling proteins UCP2 and UCP3 are elementary for mitochondrial Ca²⁺ uniport albeit a definite molecular identification of the MCU has not been completed yet.

Currently, we integrate these findings to a novel concept that describes distinct characteristics of mitochondrial Ca²⁺ uptake in intact cells depending on the source and mode of cytosolic Ca²⁺ elevation. Using siRNA induced knock-down of UCP2 and UCP3 it emerges that mitochondrial Ca²⁺ uptake upon IP₃-induced Ca²⁺ release is mainly under the control of the UCP2/3 dependent MCU, whereas the transfer of entering Ca²⁺ into mitochondria is accomplished via an UCP2/3 independent pathway. However, increased levels of these UCPs dramatically enforced the mitochondrial Ca²⁺ uptake of entering Ca²⁺, whereas an expression of mutated UCPs reduced exclusively mitochondrial Ca²⁺ signals that were fueled by Ca²⁺ entry. These studies demonstrate the importance of UCP expression levels as a determinant of the magnitude and velocity of mitochondrial Ca²⁺ sequestration pending on the Ca²⁺ source and point to the existence of molecularly distinct mitochondrial Ca²⁺ uptake sites facing either sites of ER Ca²⁺ release or Ca²⁺ entry. Although we are only at the beginning to characterize and understand the functioning of different molecular components of distinct sites of mitochondrial Ca²⁺ uptake, it occurs that these different mitochondrial Ca²⁺ uptake sites match the different functional properties of local and global Ca²⁺ events at sites of ER Ca²⁺ release and those of Ca²⁺ entry in order to properly integrate different Ca²⁺ signals into many vitally cellular processes.