Fig. 1: Ca²⁺ signaling at the ER and the mitochondria in cell death and survival.

Arrow-headed lines indicate a stimulatory or consequential effect. The ER is the main intracellular Ca²⁺ storage organelle. The release of Ca²⁺ from this organelle is mediated by the IP₃R, gated by the intracellular messenger IP₃. Ca²⁺ then travels via VDAC1, which is physically coupled to the IP₃R through GRP75, and MCU to the mitochondrial matrix. Ca²⁺ oscillations targeted to the mitochondria are able to stimulate mitochondrial metabolism in several ways. Firstly, the TCA cycle has three rate-limiting enzymes that are regulated by Ca²⁺: pyruvate dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. Furthermore, both the ATP synthase and complex III of the electron transport chain (ETC) are stimulated by Ca²⁺. In addition, the adenine nucleotide translocase (ANT) is activated as well. Interestingly, positive feedback mechanisms exist to ensure Ca²⁺ feeding into the mitochondria. One of these mechanisms is dependent on a redox-nano-domain at the MAMs: Ca²⁺ influx into the mitochondrial matrix activates Ca²⁺-activated K⁺ channels and parallel H₂O uptake in the mitochondria. This results in cristae compression (indicated by the red arrows) and H₂O₂ extrusion, which stimulates IP₃R activity. In short, by stimulating cellular metabolism, Ca²⁺ oscillations contribute to cell survival. However, excessive Ca²⁺ uptake in the mitochondria causes mitochondrial Ca²⁺ overload. This results in opening of the mPTP, either by a direct action of Ca²⁺ on the mPTP or by Ca²⁺ binding to cardiolipin, thereby disrupting complex II of the ETC and subsequent ROS production. mPTP opening leads to mitochondrial swelling, rupture of the OMM, and release of pro-apoptotic factors like cytochrome c and ultimately apoptosis