Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species.

  title={Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species.},
  author={Clara J. Schroedl and David S McClintock and G R Scott Budinger and Navdeep S. Chandel},
  journal={American journal of physiology. Lung cellular and molecular physiology},
  volume={283 5},
The molecular mechanisms by which cells detect hypoxia (1.5% O2), resulting in the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha) protein remain unclear. One model proposes that mitochondrial generation of reactive oxygen species is required to stabilize HIF-1alpha protein. Primary evidence for this model comes from the observation that cells treated with complex I inhibitors, such as rotenone, or cells that lack mitochondrial DNA (rho(0)-cells) fail to generate reactive oxygen… 

Stabilization of Hypoxia-inducible Factor-1α Protein in Hypoxia Occurs Independently of Mitochondrial Reactive Oxygen Species Production*

It is concluded that HIF-1α protein stabilization in hypoxia occurs independently of mitochondrial ROS production, however, mitochondria can modulate the cellular hypoxic response through altered respiratory activity, likely by regulating the cellular oxygen availability.

Mitochondrial Reactive Oxygen Species are Required for Hypoxic HIFα Stabilization

It is demonstrated that mitochondrial reactive O2 species (ROS) are essential for O2 sensing and subsequent HIFα stabilization at 1.5% O2 and that exogenous treatment with H2O2 and severe O2 deprivation is sufficient to stabilize HIF α even in the absence of functional mitochondrial.

Mitochondrial Reactive Oxygen Species Activation of p38 Mitogen-Activated Protein Kinase Is Required for Hypoxia Signaling

Genetic evidence is provided that p38 mitogen-activated protein kinase signaling is essential for HIF-1 activation, and the activation of p38α and Hif-1 is dependent on the generation of mitochondrial reactive oxygen species.

Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers

The results indicate that functional mitochondria are important in Hif-1α and HIF-2α protein stability and transcriptional activity during normoxia as well as in hypoxia, and that mitochondrial uncouplers may be useful in the inhibition of HIF pathway in tumors.

Nitric oxide produced endogenously is responsible for hypoxia-induced HIF-1α stabilization in colon carcinoma cells.

The results support a regulatory mechanism of HIF-1α during hypoxia in which endogenously generated NO and ROS promote inhibition of PHD2 activity, probably by its S-nitrosation.

Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation.

Hypoxic reduction in cellular glutathione levels requires mitochondrial reactive oxygen species.

A novel HIF-independent role for mitochondrial ROS in regulating glutathione synthesis, and hence cellular oxidative homeostasis, during hypoxic exposure is suggested.

Induction of HIF-2alpha is dependent on mitochondrial O2 consumption in an O2-sensitive adrenomedullary chromaffin cell line.

During low O2 (hypoxia), hypoxia-inducible factor (HIF)-alpha is stabilized and translocates to the nucleus, where it regulates genes critical for survival and/or adaptation in low O2. While it



Reactive Oxygen Species Generated at Mitochondrial Complex III Stabilize Hypoxia-inducible Factor-1α during Hypoxia

Findings reveal that mitochondria-derived ROS are both required and sufficient to initiate HIF-1α stabilization during hypoxia and that catalase abolishes hypoxic response element-luciferase expression during Hypoxia.

Oxygen Sensing and HIF-1 Activation Does Not Require an Active Mitochondrial Respiratory Chain Electron-transfer Pathway*

It is found that mitochondrial DNA-less (ρo) cells have a normal response to hypoxia, measured at the level of HIF-1α protein stabilization, nuclear translocation, and its transcriptional activation activity.

Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain.

Data do not support the model outlined above and indicate that a functional respiratory chain is not necessary for the regulation of HIF by oxygen.

The Role of Mitochondria in the Regulation of Hypoxia-inducible Factor 1 Expression during Hypoxia*

It is suggested that electron transport chain activity is required for activation of HIF-1, a heterodimeric transcription factor that regulates transcriptional activation of several genes responsive to the lack of oxygen.

Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension.

Results provide evidence for the involvement of HIF-1 in O2 homeostasis and represent a functional characterization of the putative O2 sensor that initiates hypoxia signal transduction leading to Hif-1 expression.

A protective role for HIF-1 in response to redox manipulation and glucose deprivation: implications for tumorigenesis

It is demonstrated that HIF-1α deficient cells are less tumorigenic than wild-type cells and showed a reduced growth rate when grown as xenografts in nude mice, suggesting that HIFT may have a protective role in adaptation to the tumour micro-environment.

Mitochondrial reactive oxygen species trigger hypoxia-induced transcription.

Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl2) in Hep3B cells. However,

Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells.

It is reported here that HIF-1alpha protein levels are strongly increased by fetal calf serum in quiescent VSMC, and strong induction of VEGF mRNA by Ang II can also be inhibited by these ROS inhibitors.

Induction of hypoxia-inducible factor-1, erythropoietin, vascular endothelial growth factor, and glucose transporter-1 by hypoxia: evidence against a regulatory role for Src kinase.

Results indicate that src is not critical for the hypoxic induction of HIF-1, erythropoietin, VEGF, or Glut-1 and that the expression of these genes in src- or c-src kinase-deficient cells did not differ from wild-type cells at either 1% oxygen or more severe hypoxia.

The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis

It is indicated that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF α-subunits, which may underlie the angiogenic phenotype of VHL-associated tumours.