Mitochondria as all‐round players of the calcium game (original) (raw)

Although it has been known for over three decades that mitochondria are endowed with a complex array of Ca¥ transporters and that key enzymes of mitochondrial metabolism are regulated by Ca¥, the possibility that physiological stimuli that raise the [Ca¥] of the cytoplasm could trigger major mitochondrial Ca¥ uptake has long been considered unlikely, based on the low affinity of the mitochondrial transporters and the limited amplitude of the cytoplasmic [Ca¥] rises. The direct measurement of mitochondrial [Ca¥] with highly selective probes has led to a complete reversion of this view, by demonstrating that, after cell stimulation, the cytoplasmic Ca¥ signal is always paralleled by a much larger rise in [Ca¥] in the mitochondrial matrix. This observation has rejuvenated the study of mitochondrial Ca¥ transport and novel, unexpected results have altered long-standing dogmas in the field of calcium signalling. Here we focus on four main topics: (i) the current knowledge of the functional properties of the Ca¥ transporters and of the thermodynamic constraints under which they operate; (ii) the occurrence of mitochondrial Ca¥ uptake in living cells and the key role of local signalling routes between the mitochondria and the Ca¥ sources; (iii) the physiological consequences of Ca¥ transport for both mitochondrial function and the modulation of the cytoplasmic Ca¥ signal; and (iv) evidence that alterations of mitochondrial Ca¥ signalling may occur in pathophysiological conditions.