A targeted antioxidant reveals the importance of mitochondrial reactive oxygen species in the hypoxic signaling of HIF-1α

Exposure to limiting oxygen in cells and tissues induce the stabilization and transcriptional activation of the hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein, a key regulator of the hypoxic response. Reactive oxygen species (ROS) generation has been implicated in the stabilization of HIF-1 alpha 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-1 alpha. Our results show that under conditions of reduced oxygen (3% O-2), MitoQ ablated the hypoxic induction of ROS generation and destabilized HIF-1 alpha protein. This in turn led to an abrogation of HIF-1 transcriptional activity. Normoxic stabilization of HIF-1 alpha, 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-1 alpha. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.