Metabolic Key to Hypoxia Tolerance: Loss of Regulatory Links Between the Electron Transfer System and Glycolysis

Abstract

The aerobic metabolic rates of cells, tissues, and even whole organisms display two kinds of responses to O2 availability: Respiration rates either (i) remain relatively constant down to very low values (O2 regulating response) or (ii) decline steadily with O2 availability (O2 conforming response). That is, the apparent Km values for O2 in the two repsonses differ widely. In O2 regulators, once respiration does begin to fall, key metabolite signals (such as ATP/ADP ratios or free ADP concentration per se) serve as regulatory links between the electron transfer system (ETS) and glycolysis, assuring phasing in of the latter as the former is phased out. These regulatory connections between the ETS and glycolysis cause the Pasteur effect which typically involves 5–15 fold increases in glucose consumption rates as the system attempts to make up the hypoxia-based energy deficit. In O2 conformers, the regulatory linkage between the ETS and glycolysis is seemingly broken. In extreme versions of this response (e.g. some lungfish tissues), there are no discernible changes in creatine phosphate or adenylate concentrations, in redox state, or in lactate formation under severely hypoxic conditions. This means that O2 conformers do not make up the energy deficit caused by ETS blockade and thus enter a metabolically arrested state when O2 is limiting; i.e., respiration falls without a concomitant Pasteur effect. What signal guides the O2 conforming system “down the O2 saturation curve”? The answer to this question is not known, but current evidence suggests that the ETS is “sensing” O2 availability per se; as the latter decreases, respiration rates decline.