Oxygen versus Reactive Oxygen in the Regulation of HIF-1: The Balance Tips
Figure 1
Mitochondria-dependent control of intracellular oxygen and ROS levels and its role in the regulation of HIF-1α. Mitochondria, via complex IV of the electron transport chain, are the major consumers of cellular oxygen. Under conditions of limiting oxygen diffusion, mitochondrial respiratory activity therefore exerts control over the intracellular oxygen concentration. Consistently, gradients in the oxygen concentration between extracellular space, cytoplasm, and perimitochondrial space have been observed [34, 35]. Changes in the intracellular oxygen concentration are sensed by oxygen-dependent dioxygenase enzymes, prolyl hydroxylase domain enzymes (PHD), and the asparagine hydroxylase Factor Inhibiting HIF (FIH). The major target of these two oxygen sensing enzyme classes is the transcription factor Hypoxia Inducible Factor-1α (HIF-1α). PHD enzymes and FIH hydroxylate HIF-1α at specific proline and asparagine residues to induce HIF-1α protein ubiquitination and degradation and inhibit its transcriptional activity, respectively. Under low oxygen conditions, PHD and FIH are inhibited, hence leading to activation of the hypoxic response. In most cell types in addition to consuming oxygen, the mitochondrial electron transport chain is also the major producer of superoxide which is converted into membrane permeable and diffusible H2O2 by Superoxide Dismutase 1 and 2 (SOD1 and SOD2). It has been proposed that mitochondrial production of ROS derived from respiratory complex III is increased under hypoxia, and these ROS contribute to HIF-1α protein stabilization by inhibiting PHD enzymes. However, recent studies indicate that PHD enzymes have very low sensitivity to H2O2 while FIH is much more susceptible to inactivation by peroxide [18]. Furthermore, it has been shown that hypoxia leads to downregulation of thioredoxin reductase 1 (TR1) and consequently to increased intracellular H2O2 concentrations [17]. However, manipulation of TR1 expression in hypoxia was without effects on HIF-1α accumulation and activation. These results provide further support that PHD activity towards HIF-1α in hypoxia is primarily controlled by intracellular oxygen concentrations.
