Journal of Aging Research / 2011 / Article / Fig 1

Review Article

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.

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