Mitochondrial Ca(2+) as a key regulator of mitochondrial activities

Mitochondria play a central role in cell biology, not only as producers of ATP but also as regulators of the Ca(2+) signal. The translocation by respiratory chain protein complexes of H(+) across the ion-impermeable inner membrane generates a very large H(+) electrochemical gradient that can be employed not only by the H(+) ATPase to run the endoergonic reaction of ADP phosphorylation, but also to accumulate cations into the matrix. Mitochondria can rapidly take up Ca(2+) through an electrogenic pathway, the uniporter, that acts to equilibrate Ca(2+) with its electrochemical gradient, and thus accumulates the cation into the matrix, and they can release it through two exchangers (with H(+) and Na(+), mostly expressed in non-excitable and excitable cells, respectively), that utilize the electrochemical gradient of the monovalent cations to prevent the attainment of electrical equilibrium.The uniporter, due to its low Ca(2+) affinity, demands high local Ca(2+) concentrations to work. In different cell systems these high Ca(2+) concentration microdomains are generated, upon cell stimulation, in proximity of the plasma membrane and the sarco/endoplasmic reticulum Ca(2+) channels.Recent work has revealed the central role of mitochondria in signal transduction pathways: evidence is accumulating that, by taking up Ca(2+), they not only modulate mitochondrial activities but also tune the cytosolic Ca(2+) signals and their related functions. This review analyses recent developments in the area of mitochondrial Ca(2+) signalling and attempts to summarize cell physiology aspects of the mitochondrial Ca(2+) transport machinery.