The role of mitochondrial potential in control of calcium signals involved in cell proliferation.

Store-operated Ca2+ entry (SOCE), a Ca2+ influx pathway involved in cell proliferation, depends on mitochondrial Ca2+ uptake, a Ca2+ influx that is driven by the mitochondrial potential (DeltaPsi). Whereas much attention has been paid to the Ca2+-dependence of mitochondrial Ca2+ uptake, its dependence on DeltaPsi remains largely in qualitative terms. We have studied the dose-dependent effects of a mild mitochondrial uncoupler, salicylate, on DeltaPsi, mitochondrial Ca2+ concentration ([Ca2+]mit), SOCE and cell proliferation by fluorescence microscopy and photon counting of cells expressing a low-affinity aequorin targeted to mitochondria. These data and a novel algorithm to convert fluorescence values of tetramethylrhodamine (TMR) probes into millivolts provide the opportunity of quantifying the relationship among the above parameters. We found that a small mitochondrial depolarisation is sufficient to inhibit largely mitochondrial Ca2+ uptake, leading to SOCE inactivation and prevention of cell proliferation. Conversely, mitochondrial hyperpolarisation increased the activity of the Ca2+-dependent transcription factor NFAT and promoted cell proliferation. Thus, small changes in DeltaPsi influence largely Ca2+ uptake by mitochondria, cytosolic Ca2+ signals and the downstream signalling pathway to cell proliferation.