Mark Wefers Bettink

Chapter 2 24 Metabolic adaptation Two important metabolic adaptation mechanisms that may protect a cell from an energy crisis due to reduced oxygen delivery have been described in literature. One is ametabolic shift from aerobic oxidative phosphorylation to an-aerobic glycolysis also referred to as metabolic reprogramming (18). The other is oxygen conformance, which Arthur et al. (19) described as “the ability to reduce energy demand, and hence oxygen consumption, in response to a decline in oxygen availability without a decrease in the concentration of ATP”. Although it is likely that both mechanisms play a role in the adaptation to the reduced supply of oxygen, here the focus will be on oxygen conformance. Although the mechanism of oxygen conformance was already mentioned by Peter Hochachka in 1986 (20) it was not until 1993 that Schumacker et al. (21) described a decrease in oxygen consumption in primary rat hepatocytes in response to moderate oxygen (20-50mmHg) deprivation. They showed that the duration of hypoxia and the time period in which oxygen levels were decreased was important for the cellular response, i.e. whether the cells reduced their oxygen consumption rate or not. Before their report, studies had always used a quick depletion of oxygen usually for a short period (several minutes) and shown that the rate of oxygen consumption was oxygen-independent till a PO 2 of a few mmHg (22,23). Schumacker et al. (21) confirmed these previous results and showed that in primary rat hepatocytes in which PO 2 was rapidly reduced (100 to 0 mmHg in < 40 min, oxygen consumption did not change till PO 2 was less than 10 mmHg and ATP levels were preserved. In contrast, when PO 2 levels were slowly reduced ( > 2 hr) changes in oxygen consumption already occurred around 70 mmHg with a ~45% decrease in oxygen consumption around 15 mmHg. ATP levels followed the drop in oxygen consumption while NAD(P)H levels increased compared to rapidly deoxygenated cells. At low O 2 tensions of around 20 mmHg the reduced oxygen consumption could be maintained for 18 hours without a decrease in cell viability. The fact that cell viability was preserved during prolonged hypoxia in the slow hypoxia group indicates that the balance between ATP production and consumption was maintained and therefore the cells use less ATP. In a follow-up study Subramanian et al. (24) measured the changes in metabolic demand for ATP during oxygen conformance. They hypothesized whether viability was maintained by preferentially suppressing non-essential processes while leaving essential processes involved in cell homeostasis intact. They confirmed their hypothesis by showing that the non-essential processes of ATP-dependent glucuronidation and sulfation of