Models of intracellular calcium signaling network and mitochondrial calcium regulation of cellular bioenergetics in wt, PC1KD, and calcimimetic-treated PC1KD cells. Mitochondria are main players in calcium signaling network, skillful in regulating both the extent and the spatial/temporal Ca2+ signals. The membrane micro-domains between the ER and mitochondria -named Mitochondria Associated Membranes (MAMs)- are critical for an efficacy inter-organelle crosstalk (Rieusset, 2018). Several proteins, including IP3R, grp75, and VDAC, are involved in Ca2+ release from the ER, ensuring an active mitochondrial Ca2+ uptake. The mitochondrial Ca2+ uniporter (MCU) and the H+/Ca2+ exchanger (LETM1) mediate the Ca2+ uptake from cytosol inside mitochondria; conversely, the mitochondrial Na+/Ca2+ exchanger (NCLX), catalyzes the mitochondrial Ca2+ export. Inside the mitochondrion are schematized the interactions of matrix Ca2+ with processes involved in oxidative phosphorylation. The red arrows from Ca2+ to the different protein targets indicate either a direct or indirect modulating effect on their enzymatic or transport activities. Under basal conditions, PC1KD cells show lower mitochondrial Ca2+ levels with respect to wt, associated to a multilevel inhibition of OXPHOS apparatus, leading to a severe deficit of mitochondrial ATP production and cellular energy status. CaSR stimulation with the calcimimetic NPS-R568 rises intracellular calcium levels triggering the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) which drives Ca2+ from the cytosol to the lumen of the ER. CaSR activation prompts phospholipase C (PLC), a phosphodiesterase responsible for the hydrolysis of phosphatidylinositol 4,5-biphosphate to acil-glycerol and inositol 3 phosphate (IP3). The binding of IP3 to its receptor IP3R induces Ca2+ release from ER and transfer of Ca2+ from ER to mitochondria at the contact sites between ER and mitochondria. CaSR activation by calcimimetic increases mitochondrial Ca2+ levels and full restores the bioenergetics deficit in PC1KD. Enzyme, channel, and carrier abbreviations: PDH, pyruvate dehydrogenase; CS, citrate synthase; ACase, aconitase; IDH, isocitrate dehydrogenase; OGDH, oxoglutarate dehydrogenase; SCS, succinyl CoA synthase; SDH, succinate dehydrogenase (component of Complex II); Fase, fumarase; MDH, malate dehydrogenase; VDAC, voltage-dependent anion channel; ANT, adenine nucleotide translocator; IP3R, inositol 3-phosphate receptor. The complexes of oxidative phosphorylation are labeled as roman numerals from I to IV.