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

@article{Schroedl2002HypoxicBN,
  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},
  year={2002},
  volume={283 5},
  pages={
          L922-31
        }
}
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
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