FEBS Letters · 2005 · 145 citations · 34 references
Life SciencesBiochemistryCell BiologyMetabolismMitochondrial BiologyRedox BiochemistryCellular Responses To HypoxiaHypoxia AdaptationMitochondrial PhysiologyOxidative StressReactive Oxygen SpeciesRedox SignalingAntioxidant PropertiesHif-1 Alpha RegulationHypoxia-inducible Factor ActivationHypoxia-inducible Factor RegulationMitochondrial Oxidative StressReactive Oxygen Species GenerationRedox Signaling In HypoxiaTranscriptional Activation
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.
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A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF
Richard K. Bruick, Steven L. McKnight · Science · 2001 · 2.5K citations