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 autonomous. Perhaps the most ancient of the cell-autonomous adaptations to
hypoxia is a metabolic one: the Pasteur effect, which includes decreased oxidative phosphorylation and an increase in anaerobic fermentation. Because anaerobic fermentation produces far less
ATP than oxidative phosphorylation per molecule of
glucose, increased activity of the glycolytic pathway is necessary to maintain free
ATP levels in the hypoxic cell. Here, we present genetic and biochemical evidence that, in mammalian cells, this metabolic switch is regulated by the
transcription factor HIF-1. As a result, cells lacking HIF-1alpha exhibit decreased growth rates during
hypoxia, as well as decreased levels of
lactic acid production and decreased
acidosis. We show that this decrease in glycolytic capacity results in dramatically lowered free
ATP levels in HIF-1alpha-deficient hypoxic cells. Thus, HIF-1 activation is an essential control
element of the metabolic state during
hypoxia; this requirement has important implications for the regulation of cell growth during development, angiogenesis, and
vascular injury.