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

Figure 5

Network of interactions between sirtuins, p66^Shc, Ca²⁺, and ROS, which affect mitochondrial function, autophagy, and apoptosis, thereby controlling aging-dependent processes. (a) Ca²⁺ signals may increase or prevent aging. Ca²⁺ signals are characterized by different spatiotemporal characteristics and subsequently different outcomes on mitochondrial function, autophagy, and apoptosis. For example, a constitutive Ca²⁺ transfer from ER to mitochondria would stimulate mitochondrial function and inhibit autophagy and apoptosis, while a mitochondrial Ca²⁺ overload would be proapoptotic. The interplay between mitochondrial Ca²⁺ elevations and ROS production is a critical determinant in the apoptotic outcome at the level of the mitochondria, which function as co-incidence detectors. Therefore, high mitochondrial Ca²⁺ concentrations and ROS act as a double-hit mechanism, triggering mitochondrial-dependent apoptosis. (b) Sirtuins are mainly antiaging genes via the promotion of mitochondrial function and autophagy and inhibition of apoptosis. They also act inhibitingly on ROS. Sirtuin function may be enhanced by restricting caloric intake or increasing physical activity, thereby extending lifespan. Increased ROS activate the Pin1- p66^Shc complex, which, in turn, promotes the production of ROS and subsequently mitochondrial damage. Therefore, p66^Shc may help to target damaged mitochondria and activate cellular processes that deal with dysfunctional mitochondria and oxidative stress. The outcome, however, can be dual: aging may be enhanced via a complete removal of the cell through apoptosis, while the selective removal of the damaged mitochondria through mitophagy, leaving the cell with predominantly healthy mitochondria, may slow down the aging process. Green arrows: stimulation; red lines: inhibition; black arrows: stimulation or inhibition.

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