OXYGEN SENSING AND SIGNAL-TRANSDUCTION IN METABOLIC DEFENSE AGAINST HYPOXIA - LESSONS FROM VERTEBRATE FACULTATIVE ANAEROBES

Earlier studies identified two main defense strategies against hypoxia in hypoxia tolerant animals: (1) reduction in energy turnover, and (2 ) improved energetic efficiency of those metabolic processes that rema in. We used two model systems from the highly anoxia-tolerant aquatic turtle: (1) tissue slices of brain cortex (to probe cell level electro physiological responses to oxygen limitation), and (2) isolated liver hepatocytes (to probe signalling and defense). In the latter, a cascad e of processes underpinning hypoxia defense begins with an oxygen sens or that is probably a heme protein and a signal transduction pathway t hat leads to the specific activation of some genes (increased expressi on of several proteins) and to specific down regulation of other genes (decreased expression of several other proteins). The pathway seems t o have characteristics in common with oxygen regulated control element s in other cells. The probable roles of the oxygen sensing and signal transduction system include coordinate down-regulation of energy deman d and energy supply pathways in metabolism. Because of this coordinati on, hypoxia tolerant cells stay in energy balance even as they down-re gulate to extremely low levels of ATP turnover. The main ATP-demanding processes in normoxia (protein synthesis, protein degradation, glucos e synthesis, urea synthesis and maintenance of electrochemical gradien ts) are all turned down to variable degrees during anoxia or extreme h ypoxia. Most striking is the observation that ion pumping is the main energy sink in anoxia-despite reductions in cell membrane permeability (''channel arrest''). Neurons also show a much lower permeability tha n do homologous mammalian cells but, in this case under acute anoxia, there is no further change in cell membrane conductivity. We consider that, through this recent work, it is becoming evident how normoxic ma intenance ATP turnover rates can be down-regulated by an order of magn itude or more-to a new hypometabolic steady state that is prerequisite for surviving prolonged hypoxia or anoxia. The implications of these developments extend to many facets of biology and medicine. (C) 1997 E lsevier Science Inc.