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. 2012:2012:436981.
doi: 10.1155/2012/436981. Epub 2012 Oct 9.

Oxygen versus Reactive Oxygen in the Regulation of HIF-1α: The Balance Tips

Thilo Hagen  1
Affiliations

Oxygen versus Reactive Oxygen in the Regulation of HIF-1α: The Balance Tips

Thilo Hagen. Biochem Res Int. 2012.

Abstract

Hypoxia inducible factor (HIF) is known as the master regulator of the cellular response to hypoxia and is of pivotal importance during development as well as in human disease, particularly in cancer. It is composed of a constitutively expressed β subunit (HIF-1β) and an oxygen-regulated α subunit (HIF-1α and HIF-2α), whose stability is tightly controlled by a family of oxygen- and iron-dependent prolyl hydroxylase enzymes. Whether or not mitochondria-derived reactive oxygen species (ROS) are involved in the regulation of Hypoxia Inducible Factor-1α has been a matter of contention for the last 10 years, with equally compelling evidence in favor and against their contribution. A number of recent papers appear to tip the balance against a role for ROS. Thus, it has been demonstrated that HIF prolyl hydroxylases are unlikely to be physiological targets of ROS and that the increase in ROS that is associated with downregulation of Thioredoxin Reductase in hypoxia does not affect HIF-1α stabilization. Finally, the protein CHCHD4, which modulates cellular HIF-1α concentrations by promoting mitochondrial electron transport chain activity, has been proposed to exert its regulatory effect by affecting cellular oxygen availability. These reports are consistent with the hypothesis that mitochondria play a critical role in the regulation of HIF-1α by controlling intracellular oxygen concentrations.

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Figures

Figure 1
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.
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