Modulation of Calcium Entry by Mitochondria

Abstract

The role of mitochondria in intracellular Ca²⁺ signaling relies mainly in its capacity to take up Ca²⁺ from the cytosol and thus modulate the cytosolic [Ca²⁺]. Because of the low Ca²⁺-affinity of the mitochondrial Ca²⁺-uptake system, this organelle appears specially adapted to take up Ca²⁺ from local high-Ca²⁺ microdomains and not from the bulk cytosol. Mitochondria would then act as local Ca²⁺ buffers in cellular regions where high-Ca²⁺ microdomains form, that is, mainly close to the cytosolic mouth of Ca²⁺ channels, both in the plasma membrane and in the endoplasmic reticulum (ER). One of the first targets proposed already in the 1990s to be regulated in this way by mitochondria were the store-operated Ca²⁺ channels (SOCE). Mitochondria, by taking up Ca²⁺ from the region around the cytosolic mouth of the SOCE channels, would prevent its slow Ca²⁺-dependent inactivation, thus keeping them active for longer. Since then, evidence for this mechanism has accumulated mainly in immunitary cells, where mitochondria actually move towards the immune synapse during T cell activation. However, in many other cell types the available data indicate that the close apposition between plasma and ER membranes occurring during SOCE activation precludes mitochondria from getting close to the Ca²⁺-entry sites. Alternative pathways for mitochondrial modulation of SOCE, both Ca²⁺-dependent and Ca²⁺-independent, have also been proposed, but further work will be required to elucidate the actual mechanisms at work. Hopefully, the recent knowledge of the molecular nature of the mitochondrial Ca²⁺ uniporter will allow soon more precise studies on this matter.