UNIFYING THEORY OF HYPOXIA TOLERANCE - MOLECULAR METABOLIC DEFENSE AND RESCUE MECHANISMS FOR SURVIVING OXYGEN LACK

We develop a unifying theory of hypoxia tolerance based on information from two cell level models (brain cortical cells and isolated hepatoc ytes) from the highly anoxia tolerant aquatic turtle and from other mo re hypoxia sensitive systems, We propose that the response of hypoxia tolerant systems to oxygen lack occurs in two phases (defense and resc ue), The first lines of defense against hypoxia include a balanced sup pression of ATP-demand and ATP-supply pathways; this regulation stabil izes (adenylates) at new steady-state levels even while ATP turnover r ates greatly decline. The ATP demands of ion pumping are down-regulate d by generalized ''channel'' arrest in hepatocytes and by ''spike'' ar rest in neurons. Hypoxic ATP demands of protein synthesis are down-reg ulated probably by translational arrest. In hypoxia sensitive cells th is translational arrest seems irreversible, but hypoxia-tolerant syste ms activate ''rescue'' mechanisms if the period of oxygen lack is exte nded by preferentially regulating the expression of several proteins. In these cells, a cascade of processes underpinning hypoxia rescue and defense begins with an oxygen sensor (a heme protein) and a signal-tr ansduction pathway, which leads to significant gene-based metabolic re programming-the rescue process-with maintained down-regulation of ener gy-demand and energy-supply pathways in metabolism throughout the hypo xic period. This recent work begins to clarify how normoxic maintenanc e ATP turnover rates can be drastically (10-fold) down regulated to a new hypometabolic steady state, which is prerequisite for surviving pr olonged hypoxia or anoxia. The implications of these developments are extensive in biology and medicine.