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

Figure 3

Ca²⁺ signalling and key events involved in aging. Aging cells display decreased function or expression of ER proteins (IP₃Rs, RyRs, SERCAs, Ca²⁺-binding chaperones (CaBC)), increased cytosolic [Ca²⁺], suppressed agonist-mediated signaling, and accumulation of damaged mitochondria due to declined autophagic activity. The simultaneous increase in disorganization and dysfunction of the Ca²⁺-handling proteins and the decline in autophagy will result in the exaggerated production and excessive accumulation of ROS. These events may lead to both ER stress and mitochondrial dysfunction, like PTP opening and OMM permeabilization with the consequent release of apoptogenic factors and cell death. p66^Shc and sirtuins take part in this scenario. P66^Shc translocates to mitochondria upon oxidative-stress-induced PKCβ phosphorylation and peptidylprolyl isomerization by Pin1, thereby supporting ROS production. Sirtuins are downregulated and unable to exert its antiaging effect. It is important to note that while p66^Shc ablation leads to lifespan extension, high levels of p66^Shc have been observed in centenarians. While in normal cells, ROS help to detect and remove altered mitochondria through autophagy, thereby maintaining cellular health, the excessive release of ROS in combination with the decline in autophagy observed during aging may underpin the age-related cell-death processes. In this respect, the recently identified inhibitors of EGF-receptor signaling, the high-performance advanced age phenotype proteins (HPA-1 and HPA-2), whose knockdown promotes locomotory health span of C. elegans, may point towards an important role of proper agonist-induced Ca²⁺ signaling via the IP₃R axis. The relevance of these ligands or of attenuated agonist-induced signaling in humans needs to be established. However, recent evidence indicates that dysfunction of IP₃Rs during ER stress promotes cell death and underlies a neurodegenerative disease, like Huntington’s disease. Given the central role of proper IP₃R function for mitochondrial bioenergetics and ATP production, the decline of IP₃R activity observed during ER stress or attenuated upstream signaling linked to IP₃ may be very relevant for age-related apoptosis but require further investigation. Green arrows: stimulation; red lines: inhibition; black arrows: Ca²⁺ flux; dashed-green arrow: stimulation/damage.