Mitochondrial Ca²⁺ uptake by the Ca²⁺ uniporter depends exponentially on the surrounding cytosolic Ca²⁺ concentration. Thus, Ca²⁺ microdomains around Ca²⁺ channels at the plasma membrane or endomembranes favour Ca²⁺ accumulation by nearby mitochondria. By taking Ca²⁺ , mitochondria are able to dampen Ca²⁺ microdomains and remove the Ca²⁺ -dependent inactivation of store-operated Ca²⁺ entry (SOCE), a Ca²⁺ entry pathway essential for cell proliferation. In addition, mitochondria Ca²⁺ uptake depends also on mitochondrial potential (DY), the driving force for Ca²⁺ accumulation inside mitochondria. However, the quantitative relationship between DY and mitochondrial Ca²⁺ uptake as well as its influence on Ca²⁺ signals remains elusive, probably because of the difficulty of monitoring both parameters in living cells in a quantitative manner. We have recently studied the dose-dependent effects of a mild mitochondrial uncoupler, salicylate, on DY, mitochondrial Ca²⁺ uptake, SOCE and cell proliferation. These data and the development of a novel algorithm to convert fluorescence values of TMR probes into DY in millivolts enables quantifying the relationship among DY, mitochondrial Ca²⁺ uptake, SOCE and cell proliferation. We found that a small mitochondrial depolarization of a few tens of millivolts is enough to inhibit largely mitochondrial Ca²⁺ uptake, leading to SOCE inactivation and prevention of cell proliferation. Conversely, mitochondrial hyperpolarisation promoted cell proliferation. In addition, transcriptional activity of the Ca²⁺ -dependent transcription factor NFAT -which is essential for cell proliferation- is regulated by DY. Thus, DY influences largely mitochondrial Ca²⁺ uptake and hence SOCE and the downstream signalling pathway to cell proliferation.

Supported by DIGICYT, CSIC and Junta de Castilla y León.