IP₃ Receptors, Mitochondria, and Ca²⁺ Signaling: Implications for Aging

Figure 1

In a healthy cell, ER Ca²⁺-handling components tightly regulate mitochondrial function and bioenergetics, representing the different key players involved in intracellular Ca²⁺ signalling with particular emphasis on the ER-mitochondria connections. The ER-Ca²⁺ content is regulated by channels and pumps (IP₃Rs, RyRs, SERCAs) and by Ca²⁺-binding chaperones (CaBCs). IP₃ stimulates ER Ca²⁺ release and consequently the transfer of Ca²⁺ (red dots) from ER to mitochondria. Mitochondrial Ca²⁺, transported via VDAC, is directly or indirectly involved in cellular energy metabolism and in the secondary production of reactive oxygen species (ROS). It is clear that IP₃R-mediated Ca²⁺ release ought to be tightly regulated to sustain mitochondrial activity and function. As a consequence, Ca²⁺-flux properties of IP₃Rs are tightly and dynamically regulated by accessory proteins involved in cell death and survival, like Bcl-2, Bcl-Xl, PKB/Akt, Sigma-1 receptor (Sig-1R)/Ankyrin B (AnkB), and the recently identified PML. It is important to note that different regulatory mechanisms occur at the IP₃R, which may help cell survival (like Bcl-2, Bcl-Xl, PKB/Akt) or help to promote cell death (like PML). The latter is essential to prevent the survival of altered, damaged, or oncogenic cells. Thus, a tight balance between both outcomes is a requisite for cellular health and homeostasis, and a dynamic switch from prosurvival to prodeath is likely essential. In this paradigm, the production of ROS might contribute to the survival of cells by efficient detection of damaged/altered mitochondria and their removal by autophagy, while preventing excessive apoptosis. In addition, controlled apoptosis is likely to be important to eliminate cells, in which the removal of altered mitocondria by autophagy is not sufficient, thereby avoiding tumor genesis. In this process, the recently identified tumor suppressor PML may play a crucial role as it promotes IP₃R-mediated Ca²⁺ transfer from the ER into the mitochondria by dephosphorylating and suppressing PKB/Akt activity through PP2A. While PKB/Akt is known to suppress IP₃R-channel activity by phosphorylation of the IP₃R, the recruitment of PP2A via PML at the interorganellar ER/mitochondrial complex dephosphorylates and inactivates PKB/Akt. This suppresses PKB-dependent phosphorylation of IP₃R and thus promotes Ca²⁺ release through this channel and Ca²⁺ transfer into the mitochondria. At the mitochondrial level, the tumor suppressor Fhit has been shown to increase the affinity for the mitochondrial Ca²⁺ uniporter (MCU), thereby enhancing the uptake of mitochondrial Ca²⁺ at low and physiologically relevant levels of agonist-induced Ca²⁺ signals. Green arrows: stimulation; red lines: inhibition; black arrows: Ca²⁺ flux.