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All animal life requires molecular oxygen as the terminal electron acceptor in aerobic energy production. A lack of oxygen can reduce the rate of energy production, whereas an excess of oxygen leads to the accumulation of toxic reactive oxygen species. Hence, animals have evolved sophisticated mechanisms with which to monitor and respond to fluctuations in oxygen availability, in order to maintain cellular homeostasis. In all animal taxa examined so far, the maintenance of physiological oxygen homeostasis is mediated by the oxygen-dependent post-translational hydroxylation of a heterodimeric transcription factor, termed hypoxia-inducible factor (HIF; Kaelin & Ratcliffe, 2008). The hydroxylation reaction is catalysed by prolyl hydroxylase (PHD) enzymes, which are direct sensors of cellular oxygen tension. Under normoxia, HIFα is hydroxylated in a PHD-dependent manner, which leads to its ubiquitination by the von Hippel–Lindau protein (VHL) and proteasomal degradation. Under hypoxia, the hydroxylase activity of PHD enzymes is inhibited, thereby allowing the stable formation of the heterodimeric HIF transcription factor and its activation. HIF is then translocated to the nucleus where it activates the transcription of numerous target genes involved in processes that enhance oxygen delivery—such as erythropoiesis and angiogenesis—or improve prospects for survival under hypoxia, by altering energy metabolism.
The evolutionary origins of this central physiological regulatory system have been unclear, as the regulatory interactions of the constituent HIF and PHD genes have not been experimentally characterized in non-bilaterian animals. In this issue of EMBO reports, the Schofield lab demonstrate that the HIF system has a regulatory oxygen-sensing function in the simplest known animal, the placozoan Trichoplax adhaerens (Loenarz et al, 2010).