Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells

The ability to respond to differential levels of oxygen is important to all respiring cells. The response to oxygen deficiency or hypoxia, takes many forms and ranges from systemic adaptations to those that are cell autonomou s. Perhaps the most ancient of the cell-autonomous adaptations to hypoxia i s a metabolic one: the Pasteur effect, which includes decreased oxidative p hosphorylation and an increase in anaerobic fermentation. Because anaerobic fermentation produces far less ATP than oxidative phosphorylation per mole cule of glucose, increased activity of the glycolytic pathway is necessary to maintain free ATP levels in the hypoxic cell, were, we present genetic a nd biochemical evidence that, in mammalian cells, this metabolic switch is regulated by the transcription factor HIF-1. As a result, cells lacking HIF -1 alpha exhibit decreased growth rates during hyposia, as well as decrease d levels of lactic acid production and decreased acidosis. We show that thi s decrease in glycolytic capacity results in dramatically lowered free ATP levels in HIF-1 alpha -efficient hypoxic cells. Thus, HIF-1 activation is a n essential control element of the metabolic state during hypoxia this requ irement has important implications for the regulation of cell growth during development, angiogenesis, and vascular injury.