Vertebrate cell death in energy-limited conditions and how to avoid it: what we might learn from mammalian hibernators and other stress-tolerant vertebrates

Abstract

Dormancy in vertebrates may expose cells to acidosis, hypoxia/anoxia, oxidative damage, and extremes in temperature. All of these insults are known to be pro-apoptotic in typical vertebrate cells, especially mammals. Since dormancy is presumably the result of a need for energy conservation, the inherent energetic demand of replenishing cells that underwent apoptosis seems at odds with this strategy. This review will discuss processes to mitigate apoptosis and how these processes might be regulated in stress-tolerant vertebrates such as mammalian hibernators. As data directly addressing such issues are scarce and often conflicting, an apparently complex regulation of apoptosis seems to be at work. For example, apoptosis is mitigated during dormancy, key signaling events including the activation of caspase-3 may still occur. However, both passive, temperature-induced depression of apoptotic signaling as well as active suppression of apoptosis appear to work in synergy in these systems. In many instances cell death is prevented by simply avoiding the cellular triggers (e.g. leakage of proteins from the mitochondria or increases in intracellular calcium) that initiate apoptotic signaling. In this review we discuss what is known about programmed cell death in these under-studied models and highlight features of their physiology that likely support survival in the face of conditions that would induce cell death in typical vertebrate cells.

A systems-level approach to understanding transcriptional regulation by p53 during mammalian hibernation

“…These processes are important during hibernation, e.g. apoptosis must be regulated during hibernation (van Breukelen et al, 2010).…”

“…These processes are important during hibernation, e.g. apoptosis must be regulated during hibernation (van Breukelen et al, 2010).At least 160 proteins have been reported to regulate p53 activity (Toledo and Wahl, 2006). During steady-state conditions, changes in mRNA or protein abundance of p53 regulatory proteins have…”

Frogs and estivation: transcriptional insights into metabolism and cell survival in a natural model of extended muscle disuse

“…Despite the adaptive value of the dormant phenotype, dormancy in vertebrates may expose cells to diverse stressors, including fluctuations in temperature or oxygen levels, acidosis, and oxidative damage (54). Moreover, because dormancy entails prolonged periods of inactivity and fasting, an expected outcome arising from organ and tissue disuse is cellular atrophy and the potential for compromised performance upon arousal.…”

Redox-Based Regulation of Apoptosis: S-Glutathionylation As a Regulatory Mechanism to Control Cell Death

“…It is tempting to speculate that S-glutathionylation of caspase-3 in HUVECs (57) may constitute a regulatory mechanism to control aberrant activation of caspase-3 due to various oxidative and metabolic stresses (11,79) in the umbilical vein (74,83). In conditions of overt inflammation, accompanied by release of TNFa, HUVECS induce de-glutathionylation of caspase-3, and subsequently undergo cell death.…”