|Title||A targeted antioxidant reveals the importance of mitochondrial reactive oxygen species in the hypoxic signaling of HIF-1alpha.|
|Publication Type||Journal Article|
|Year of Publication||2005|
|Authors||Sanjuan-Pla, A, Cervera, AM, Apostolova, N, Garcia-Bou, R, Víctor, VM, Murphy, MP, McCreath, KJ|
|Date Published||2005 May 09|
|Keywords||Antioxidants, Blotting, Western, Cell Hypoxia, Cell Line, Tumor, Fibrosarcoma, Gene Expression, Gene Targeting, Genes, Reporter, Hepatoblastoma, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Luciferases, Mitochondria, Oxygen, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Transcription Factors|
Exposure to limiting oxygen in cells and tissues induce the stabilization and transcriptional activation of the hypoxia-inducible factor 1 alpha (HIF-1alpha) protein, a key regulator of the hypoxic response. Reactive oxygen species (ROS) generation has been implicated in the stabilization of HIF-1alpha during this response, but this is still a matter of some debate. In this study we utilize a mitochondria-targeted antioxidant, mitoubiquinone (MitoQ), and examine its effects on the hypoxic stabilization of HIF-1alpha. Our results show that under conditions of reduced oxygen (3% O(2)), MitoQ ablated the hypoxic induction of ROS generation and destabilized HIF-1alpha protein. This in turn led to an abrogation of HIF-1 transcriptional activity. Normoxic stabilization of HIF-1alpha, on the other hand, was unchanged in the presence of MitoQ suggesting that ROS were not involved. This study strongly suggests that mitochondrial ROS contribute to the hypoxic stabilization of HIF-1alpha.
|Alternate Journal||FEBS Lett.|