Hypoxia and the control of protein synthesis and homeostasis in Drosophila

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Animals often live in conditions where environmental oxygen levels fluctuate As a result, they must coordinate their metabolism with changes in oxygen availability. In particular, upon oxygen deprivation, or hypoxia, animals need to alter their metabolism to limit energetically costly anabolic processes, maintain homeostasis and promote survival. Defects in this metabolic control can impair cell and tissue homeostasis and can lead to lethality.******One metabolic strategy is suppression of protein synthesis. Given that protein synthesis accounts for over a third of cellular ATP use, this suppression helps to restrict energy expenditure. Selective translational control also provides a mechanism to limit gene expression to proteins required for stress responses. Hypoxia can suppress translation and the mechanisms have been studied almost exclusively in cell culture. What is not clear is how translational control contributes to in vivo regulation of cell and tissue homeostasis in animals during hypoxia. ******The goal of this NSERC program is to examine how hypoxia regulates mRNA translation to control organismal physiology and survival, using Drosophila as a model. Drosophila can tolerate prolonged periods of low oxygen with no effects on viability. Our program has three main objectives to examine the molecular basis for this striking hypoxia tolerance:***Objective 1: To examine the effects of PERK on hypoxia tolerance. Our data suggest that hypoxia suppress translation by activating PERK kinase, which phosphorylates and inhibits eIF2alpha, an essential translation initiation factor. Moreover, we find that PERK mutants are unable to tolerate hypoxia. We will test whether PERK exerts these effects on translation and organismal survival via cell autonomous and /or cell non-autonomous mechanisms.******Objective 2: To examine effects of PERK on insulin signaling in hypoxia. Suppression of insulin signaling is a conserved regulatory response to stress in invertebrates. We find that hypoxia inhibits systemic insulin signaling in Drosophila. We will test whether this is a mechanism used by PERK to regulate hypoxia tolerance. ******Objective 3: To identify new regulators of hypoxia tolerance. This longer-term objective will use polysome profiling to identify genes whose mRNA translation is induced by hypoxia. We will then investigate these genes as potential regulators of hypoxia tolerance. These objective will provide new, long-term avenues of investigation for our program.******This NSERC grant will establish a new, exciting program of research to help understand how cells, tissues and organisms can tolerate hypoxia and maintain homeostasis and survival. ********