Mitochondria and Ca2+ signaling: old guests, new functions

Mitochondria are ancient endosymbiotic guests that joined the cells in the evolution of complex life. While the unique ability of mitochondria to produce adenosine triphosphate (ATP) and their contribution to cellular nutrition metabolism received condign attention, our understanding of the organelle’s contribution to Ca²⁺ homeostasis was restricted to serve as passive Ca²⁺ sinks that accumulate Ca²⁺ along the organelle’s negative membrane potential. This paradigm has changed radically. Nowadays, mitochondria are known to respond to environmental Ca²⁺ and to contribute actively to the regulation of spatial and temporal patterns of intracellular Ca²⁺ signaling. Accordingly, mitochondria contribute to many signal transduction pathways and are actively involved in the maintenance of capacitative Ca²⁺ entry, the accomplishment of Ca²⁺ refilling of the endoplasmic reticulum and Ca²⁺-dependent protein folding. Mitochondrial Ca²⁺ homeostasis is complex and regulated by numerous, so far, genetically unidentified Ca²⁺ channels, pumps and exchangers that concertedly accomplish the organelle’s Ca²⁺ demand. Notably, mitochondrial Ca²⁺ homeostasis and functions are crucially influenced by the organelle’s structural organization and motility that, in turn, is controlled by matrix/cytosolic Ca²⁺. This review intends to provide a condensed overview on the molecular mechanisms of mitochondrial Ca²⁺ homeostasis (uptake, buffering and storage, extrusion), its modulation by other ions, kinases and small molecules, and its contribution to cellular processes as fundamental basis for the organelle’s contribution to signaling pathways. Hence, emphasis is given to the structure-to-function and mobility-to-function relationship of the mitochondria and, thereby, bridging our most recent knowledge on mitochondria with the best-established mitochondrial function: metabolism and ATP production.