Mitochondria as all‐round players of the calcium game

Abstract

Although it has been known for over three decades that mitochondria are endowed with a complex array of Ca 2+ transporters and that key enzymes of mitochondrial metabolism are regulated by Ca 2+, the possibility that physiological stimuli that raise the [Ca 2+] of the cytoplasm could trigger major mitochondrial Ca 2+ uptake has long been considered unlikely, based on the low affinity of the mitochondrial transporters and the limited amplitude of the cytoplasmic [Ca 2+] rises. The direct measurement of mitochondrial [Ca 2+] with highly selective probes has led to a complete reversion of this view, by demonstrating that, after cell stimulation, the cytoplasmic Ca 2+ signal is always paralleled by a much larger rise in [Ca 2+] in the mitochondrial matrix. This observation has rejuvenated the study of mitochondrial Ca 2+ 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 2+ transporters and of the thermodynamic constraints under which they operate; (ii) the occurrence of mitochondrial Ca 2+ uptake in living cells and the key role of local signalling routes between the mitochondria and the Ca 2+ sources; (iii) the physiological consequences of Ca 2+ transport for both mitochondrial function and the modulation of the cytoplasmic Ca 2+ signal; and (iv) evidence that alterations of mitochondrial Ca 2+ signalling may occur in pathophysiological conditions.