Regulation of hypometabolism: insights into epigenetic controls

Abstract

For many animals, survival of severe environmental stress (e.g. to extremes of heat or cold, drought, oxygen limitation, food deprivation) is aided by entry into a hypometabolic state. Strong depression of metabolic rate, often to only 1-20% of normal resting rate, is a core survival strategy of multiple forms of hypometabolism across the animal kingdom, including hibernation, anaerobiosis, aestivation and freeze tolerance. Global biochemical controls are needed to suppress and reprioritize energy use; one such well-studied control is reversible protein phosphorylation. Recently, we turned our attention to the idea that mechanisms previously associated mainly with epigenetic regulation can also contribute to reversible suppression of gene expression in hypometabolic states. Indeed, situations as diverse as mammalian hibernation and turtle anoxia tolerance show coordinated changes in histone post-translational modifications (acetylation, phosphorylation) and activities of histone deacetylases, consistent with their use as mechanisms for suppressing gene expression during hypometabolism. Other potential mechanisms of gene silencing in hypometabolic states include altered expression of miRNAs that can provide post-transcriptional suppression of mRNA translation and the formation of ribonuclear protein bodies in the nucleus and cytoplasm to allow storage of mRNA transcripts until animals rouse themselves again. Furthermore, mechanisms first identified in epigenetic regulation (e.g. protein acetylation) are now proving to apply to many central metabolic enzymes (e.g. lactate dehydrogenase), suggesting a new layer of regulatory control that can contribute to coordinating the depression of metabolic rate.

Gene expression profiling of whole blood cells supports a more efficient mitochondrial respiration in hypoxia-challenged gilthead sea bream (Sparus aurata)

“…Consistent with [8], this finding likely reflects metabolic changes mediated by O 2 sensors that drive the shift of the redox cellular status of NADH to a more reduced form with a rapid recycling of NAD + to NADH. Certainly, hypoxic situations must improve and adjust the metabolic and O 2 -carrying capacities of challenged fish to cope and reach internal homeostasis [29]. The trigger observed in plasma antioxidant capacity after acute and severe hypoxia demonstrates a general decrease in metabolic rates that also reflects the aerobic/anaerobic shift of metabolism [25, 30, 31].…”

Characterization of the SIRT family of NAD+-dependent protein deacetylases in the context of a mammalian model of hibernation, the thirteen-lined ground squirrel

“…Numerous studies have identified diverse functions for protein deacetylases in the control of eukaryotic gene expression and cellular metabolism, including potential roles in transcriptional suppression previously implicated for Class I and II deacetylases (also known as histone deacetylases or HDACs) in the context of mammalian hibernation [30,41] and turtle anoxia tolerance [22,41]. Previous studies also hypothesized a possible role for SIRT deacetylases in the regulation of the major metabolic changes that occur over the hibernation torpor-arousal cycle, with pathways of lipid catabolism, oxidative stress resistance, and transcriptional suppression being likely candidates for regulation by SIRTs [28,32].…”

Selective inhibition of histone deacetylase 6 promotes survival in a rat model of hemorrhagic shock

“…Acetylation is rapidly emerging as a key mechanism that regulates the expression of numerous genes (epigenetic modulation through activation of nuclear histone proteins), as well as functions of multiple cytoplasmic proteins involved in key cellular functions such as cell survival, repair/healing, metabolism, signaling, and proliferation (3, 8, 9). It has been reported that, at the molecular level, hemorrhage leads to an imbalance in acetylation of proteins (hypo-acetylation of proteins compared to the normal state) and that treatment with histone deacetylase (HDAC) inhibitors can promptly restore the balance (10).…”