The chaperone machinery regulating mitochondrial Ca2+ signaling and bioenergetics. Ca2+ signaling and its regulation at the MAM are crucial for the proper functioning of mitochondria specifically regarding their roles in the bioenergetics and apoptosis. Many chaperones are known to participate in the regulation of Ca2+ transporters and channels at the MAM particularly on the Ca2+-ATPase, which uptakes Ca2+ from the cytosol into the ER and the IP3 receptor, which transmits high concentration Ca2+ ‘puffs’ into mitochondria. ERp57 collaborates with another chaperone calreticulin (CRT) to attenuate the activity of Ca2+-ATPase. ERp57 does so by modulating the redox state of the Ca2+-ATPase and thus provides dynamic control of ER Ca2+ homeostasis. Another chaperone, ERp44, can sense the environment in the ER lumen and inhibits type-1 IP3 receptors, which reside mainly outside the MAM, for instance, in CHO cells. The chaperone grp75 serves to link the VDAC and IP3 receptor, thus, shortening the distance between the MAM and the mitochondria. The cytosolic sorting protein PACS-2 can cause the translocation of calnexin chaperone from the ER to the plasma membrane, thus, indirectly affecting the Ca2+ homeostasis in the ER lumen. Another chaperone player at the MAM is the newly identified receptor chaperone called the sigma-1 receptor. Under normal, resting conditions, the sigma-1 receptor (Sig-1R) chaperone, residing specifically at the MAM, forms a complex with BiP when the ER Ca2+ concentration is 0.5-1.0 mM. Ca2+ seems to facilitate the association between the Sig-1R and BiP. The Sig-1R in the complex is essentially in a dormant state with regard to chaperone activity. When IP3 receptors are activated, however, the subsequent drop of the ER Ca2+ concentration causes the dissociation of Sig-1Rs from BiP, unleashing the chaperone activity of the receptor. In the presence of high concentrations of cytosolic IP3, activated IP3 receptors are unstable and are readily ubiquitylated and degraded by proteasomes. The free form of Sig-1Rs associates with type-3 IP3 receptors (IP3R3) at the MAM, thus, preventing IP3R3 from being degraded by proteasomes. Sig-1Rs apparently do not chaperone type-1 IP3 receptors (IP3R1) at the bulk ER membrane. The stabilization of IP3R3 by Sig-1Rs therefore ensures the proper Ca2+ influx into mitochondria, presumably leading to the enhancement of ATP production in the TCA cycle or the electron transport chain. The refilling of the ER Ca2+ pool inactivates Sig-1R chaperones by promoting the re-association of the Sig-1R with BiP. Chaperone machinery on both sides of the ER and mitochondria thus works in concert, partly by sensing the ER Ca2+ concentration, to strengthen the interaction between the ER and mitochondrion, facilitating interorganelle signal transduction, metabolic regulation and the bioenergetics of the cell.