Mitochondria as all-round players of the calcium game

Although it has been known for over three decades that mitochondria are end owed with a complex array of Ca2+ transporters and that key enzymes of mito chondrial metabolism are regulated by Ca2+, the possibility that physiologi cal stimuli that raise the [Ca2+] of the cytoplasm could trigger major mito chondrial Ca2+ uptake has long been considered unlikely, based on the low a ffinity of the mitochondrial transporters and the limited amplitude of the cytoplasmic [Ca2+] rises. The direct measurement of mitochondrial [Ca2+] wi th highly selective probes has led to a complete reversion of this view, by demonstrating that, after cell stimulation, the cytoplasmic Ca2+ signal is always paralleled by a much larger rise in [Ca2+] in the mitochondrial mat rix. This observation has rejuvenated the study of mitochondrial Ca2+ trans port and novel, unexpected results have altered long-standing dogmas in the held of calcium signalling. Here we focus on four main topics: (i) the cur rent knowledge of the functional properties of the Ca2+ transporters and of the thermodynamic constraints under which they operate; (ii) the occurrenc e of mitochondrial Ca2+ uptake in living cells and the key role of local si gnalling routes between the mitochondria and the Ca2+ sources; (iii) the ph ysiological consequences of Ca2+ transport for both mitochondrial function and the modulation of the cytoplasmic Ca2+ signal; and (iv) evidence that a lterations of mitochondrial Ca2+ signalling may occur in pathophysiological conditions.