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.
Valero
Ruth A
RA
Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and Consejo Superior de Investigaciones Científicas (CSIC), Sanz y Forés s/n, Valladolid 47003, Spain.
Senovilla
Laura
L
Núñez
Lucía
L
Villalobos
Carlos
C
D000331:Aequorin / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D049109:Cell Proliferation; D006801:Humans; D019169:Jurkat Cells; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D010080:Oxazoles / Q000378:metabolism
D000814:Aniline Compounds; C500962:Fura-4F; D010080:Oxazoles; D000331:Aequorin; D002118:Calcium