High- and low-calcium-dependent mechanisms of mitochondrial calcium signalling

SummaryThe Ca2+ coupling between endoplasmic reticulum (ER) and mitochondria is central to multiple cell survival and cell death mechanisms. Cytoplasmic [Ca2+] ([Ca2+]c) spikes and oscillations produced by ER Ca2+ release are effectively delivered to the mitochondria. Propagation of [Ca2+]c signals to the mitochondria requires the passage of Ca2+ across three membranes, namely the ER membrane, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM). Strategic positioning of the mitochondria by cytoskeletal transport and interorganellar tethers provides a means to promote the local transfer of Ca2+ between the ER membrane and OMM. In this setting, even >100 μM [Ca2+] may be attained to activate the low affinity mitochondrial Ca2+ uptake. However, a mitochondrial [Ca2+] rise has also been documented during submicromolar [Ca2+]c elevations. Evidence has been emerging that Ca2+ exerts allosteric control on the Ca2+ transport sites at each membrane, providing mechanisms that may facilitate the Ca2+ delivery to the mitochondria. Here we discuss the fundamental mechanisms of ER and mitochondrial Ca2+ transport, particularly the control of their activity by Ca2+ and evaluate both high- and low-[Ca2+]-activated mitochondrial calcium signals in the context of cell physiology.