Physiological mismatches in protein degradation and their implications for coordinated metabolic suppression during mammalian hibernation

Abstract

It is widely held that processes of both anabolism and catabolism must be equally suppressed in order to survive an extended period of metabolic depression. Mammalian hibernation is marked by sojourns to very cold body temperatures (as low as −2° C) followed by rapid returns to euthermy (36–37° C). Protein synthesis during torpor is markedly depressed in concordance with metabolic demands. Continued degradation of proteins would rapidly deplete cellular pools of key regulatory proteins and could jeapordize the animal's return to euthermy. We examined ubiquitin-mediated proteolysis which consists of two major steps: the tagging of a protein substrate by ubiquitin and the protein substrate's subsequent degradation by the 26S proteasome. There is a 2–3 fold elevation of ubiquitin conjugate concentrations during torpor: an unexpected result that seemingly would suggest increased proteolytic activity. However, the cold temperatures typical of torpor markedly reduce the degradation process. Here, we show that ubiquitylation per se continues at a moderate rate (>30% of maximal activity) at 0° C. Thus, while proteolysis is depressed during torpor as would be expected, the mechanism results in a physiological mismatch that must be resolved upon arousal. We discuss the implications of this lack of coordinated metabolic depression.