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An impressive array of organisms are capable of strongly depressing their basal metabolic rate and entering a hypometabolic state characterized by the suspension of many normal physiological functions. Metabolic rate depression is often used to elude harsh environmental conditions such as low oxygen, low temperature, or lack of water. Entry into a hypometabolic state involves the slow down or shut down of a variety of physical activities and physiological processes coordinated by molecular-level controls. At a biochemical level we have identified several mechanisms that contribute to metabolic rate depression including: 1) Reversible phosphorylation of key regulatory enzymes (e.g. phosphofructokinase, pyruvate kinase, ion motive ATPases) and functional proteins (e.g. ribosomal initiation factors) to produce less active forms, 2) Enhanced antioxidant defenses for long term survival of dormancy and to minimize damage due to rapid production of oxygen free radicals when metabolic rate rises rapidly at the end of torpor, 3) Changes in the levels of allosteric effectors of enzymes for fine control of various metabolic pathways and 4) Dissociation of enzymes from complexes bound to the subcellular particulate fraction to reduce flux through metabolic pathways. New studies have moved in different directions. Studies of signal transduction are analyzing the protein kinases and phosphatases, second messengers and transcription factors that are responsible for initiating and coordinating metabolic arrest. Studies of gene expression are identifying genes that are up-regulated during entry into or arousal from arrested states, analyzing the patterns and influences on gene expression, and investigating the roles of the associated gene products. New work has identified multiple mechanisms that participate in the global suppression of transcription in hypometabolic states including histone modification, control of RNA polymerase II, and inhibition of mRNA translation via the actions of microRNA species. The research shows that these mechanisms form a common basis for the control of metabolic rate depression across phylogeny including in the diverse animal systems that we study in lab including anoxia tolerance in turtles and marine molluscs, hibernation in small mammals, estivation in land snails and toads, and freeze tolerance in frogs, turtles and insects.
Various species of amphibians and reptiles living in temperate and polar regions of the earth survive the freezing of extracellular body fluids during the winter. The strategy is also widespread among insects and other invertebrates. Adaptations supporting freeze tolerance include: 1) Proteins: nucleating proteins induce and regulate extracellular freezing; thermal hysteresis proteins prevent recrystallization of ice, 2) Cryoprotectants: high concentrations of polyols and sugars prevent excessive cell volume reduction, increase intracellular bound water content, and stabilize proteins; trehalose and proline stabilize membrane bilayer structure, and 3) Ischemia tolerance: cells and organs have adapted to tolerate the anoxia/ischemia imposed by extracellular freezing and have good antioxidant defenses to resist oxidative stress when oxygen is suddenly reintroduced upon thawing. Our studies with freeze tolerant frogs and turtles are targeting a variety of questions that we hope will lead to applied solutions that can be used to improve the cryopreservation of human organs for transplant. New work includes a major focus on the role of gene expression in freezing survival including the identification of novel genes and their protein products whose functions are as yet unknown and the demonstration that natural freezing survival requires coordinated changes in the expression of a huge range of genes/proteins to address many different issues in cell preservation and viability. Other studies are also analyzing the roles of protein kinases and protein phosphatases in coordinating the metabolic changes that occur during freezing and determining how frog cells can endure the extremely high levels of glucose that are accumulated as a cryoprotectant, levels that would be lethal to human diabetics.
See pictures and read more about the freeze tolerant species studied in the Storey lab.
Many types of invertebrates have developed cold hardiness strategies that allow them to endure long exposures to subzero temperatures during the winter. Two strategies are possible: freeze tolerance (an ability to endure the freezing of extracellular body fluids) and freeze avoidance (an ability to remain liquid in a supercooled state at temperatures far below the freezing point of body fluids). Many insects as well as various intertidal invertebrates are freeze tolerant whereas many other types of insects and terrestrial arthropods use the freeze avoidance strategy. Adaptations supporting freeze tolerance and freeze avoidance include: 1) Protein: nucleating proteins induce and regulate extracellular freezing; antifreeze proteins inhibit ice formation, 2) Cryoprotectants: high concentrations of polyols and sugars prevent excessive cell volume reduction in freeze tolerant animals and push supercooling point to low levels in freeze avoiding animals, and 3) Metabolic arrest and ischemia tolerance: freeze tolerant animals have a well-developed tolerance for the anoxia/ischemia imposed by extracellular freezing, both strategies for winter survival include metabolic rate depression (e.g. diapause in insects) that allows long term survival using limited internal fuel reserves. Using both insect and marine mollusc models, current research is focusing on the role of gene expression in supporting cold hardiness, searching for genes that are induced or up-regulated during cooling and/or freezing and determining the role of their protein products in cold survival.
See pictures and read more about the cold hardy invertebrate species studied in the Storey lab.
Many kinds of organisms are capable of surviving extended periods without breathing oxygen. For example, turtles that hibernate underwater can live for 3-4 months without breathing whereas intertidal invertebrates that breathe with gills undergo daily bouts of oxygen deprivation with the rising and falling of the tides. Our studies of the biochemical adaptations that allow animals to live without oxygen have shown that these include the maintenance of high reserves of fermentative fuels, modified pathways of fermentative catabolism that generate a greater ATP output than glycolysis alone, mechanisms of buffering the accumulation of acidic end products, strong antioxidant defenses to resist damage to macromolecules by oxyradicals when oxygen is suddenly reintroduced, and entrance into a hypometabolic state in which organismal energy requirements are reduced by >90%. Mechanisms of metabolic rate depression are conserved across phylogenetic lines and we have shown that the same mechanisms are called into play to allow animals to elude a variety of harsh environmental conditions including low oxygen, low temperature, or lack of water (e.g. hibernation above). Our current studies of anoxia tolerance range over a variety of topics but are primarily focused on the role of anoxia-induced gene expression in animal adaptation to stress and the signal transduction pathways (signals, second messengers, protein kinases and phosphatases, nuclear transcription factors) that mediate cell responses to stress.
See pictures and read more about the anoxia-tolerant species studied in the Storey lab.