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Am J Physiol Lung Cell Mol Physiol 283: L922-L931, 2002. First published May 24, 2002; doi:10.1152/ajplung.00014.2002
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Vol. 283, Issue 5, L922-L931, November 2002

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

Clara Schroedl, David S. McClintock, G. R. Scott Budinger, and Navdeep S. Chandel

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611

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 species or stabilize HIF-1alpha protein in response to hypoxia. In the present study, we investigated the role of mitochondria in regulating HIF-1alpha protein stabilization under anoxia (0% O2). Wild-type A549 and HT1080 cells stabilized HIF-1alpha protein in response to hypoxia and anoxia. The rho 0-A549 cells and rho 0-HT1080 cells failed to accumulate HIF-1alpha protein in response to hypoxia. However, both rho 0-A549 and rho 0-HT1080 were able to stabilize HIF-1alpha protein levels in response to anoxia. Rotenone inhibited hypoxic, but not anoxic, stabilization of HIF-1alpha protein. These results indicate that a functional electron transport chain is required for hypoxic but not anoxic stabilization of HIF-1alpha protein.

rho zero; rotenone; complex I


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