Representation of intracellular Ca2+ dynamics and MAMs proteins involved in ER-mitochondria Ca2+ cross-talk. A series of protein localized in MAMs (such as PML, AKT, grp-75, SIG-1R, Mfn-1/-2, BiP, AKT) regulate Ca2+ release from the ER and an efficient mitochondrial Ca2+ uptake, resulting in different functional outcomes. Cells generate Ca2+ signal through two mechanism that use internal and external sources of Ca2+. Calcium enters into the cell through channels and pumps situated on the plasma membrane; these are gated by voltage (VOCs) or external messengers (ROCs). A series of stimuli that act on cell surface receptors triggers the activation of PLC that catalyses the hydrolysis of phosphatidylinositol 4,5-biphosphate to IP3 and DAG. The binding of IP3 to its receptor IP3R stimulates ER Ca2+ release and consequently the transfer of Ca2+ (red dots) from ER to mitochondria. Mitochondrial surface directly interacts with the ER through contact sites defining hotspot Ca2+ signalling units. Mitochondrial Ca2+ import occurs through the mitochondrial Ca2+ uniporter (MCU) and the H+/Ca2+ exchanger LETM1; conversely, NCLX, mitochondrial Na+/Ca2+ exchanger, together with the PTP, export Ca2+ from the matrix. Ca2+ levels return to resting conditions through a series of channels and pumps: PMCA and NCX permit the ion extrusion into the extracellular milieu, SERCA (situated on the ER) and SPCA (on the Golgi apparatus) re-establish basal Ca2+ levels in intracellular stores. Abbreviations: ANT, adenosine nucleoside transporter; ETC, electron transport chain; HK, hexokinase; CD, cyclophilin D; CK, creatine kinase; BR, benzodiazepine receptor.