Surviving hypoxia without really dying

In cases of severe O-2 limitation, most excitable cells of mammals cannot c ontinue to meet the energy demands of active ion transporting systems, lead ing to catastrophic membrane failure and cell death. However, in certain lo wer vertebrates, hypoxia-induced membrane destabilisation of the kind seen in mammals is either slow to develop or does not occur at all owing to adap tive decreases in membrane permeability (i.e. ion 'channel arrest'), that d ramatically reduce the energetic costs of ion-balancing ATPases. Mammalian cells do, however, exhibit a whole host of adaptive responses to less sever e shortages of oxygen, which include energy-balanced metabolic suppression, ionic-induced activation of O-2 receptors and the upregulation of certain genes,all of which enhance the systemic delivery of oxygen and promote ener gy conservation. Accumulating evidence suggests that the mechanisms underly ing these protective effects are orchestrated into action by putative membe rs of an O-2-sensing pathway that most if not all cells share in common. In this review we address three major questions: (i) how do cells detect shor tages of oxygen and subsequently set in motion adaptive mechanisms of eithe r energy production or energy conservation; (ii) how do these mechanisms re structure cellular pathways of ATP supply and demand to ensure that ion-mot ive: ATPases are given priority over other cell functions to preserve membr ane integrity in energy-limited states; and (iii) what mechanisms of molecu lar and metabolic defence against acute and long-term shortages of oxygen s et hypoxia-tolerant systems apart from their hypoxia-sensitive counterparts ? (C) 2000 Elsevier Science Inc. All rights reserved.