Molecular oxygen and carbon dioxide are the primary gaseous substrate and 
product of oxidative metabolism, respectively. Hypoxia (low oxygen) and 
hypercapnia (high carbon dioxide) are co-incidental features of the tissue 
microenvironment in a range of pathophysiologic states, including acute and 
chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master 
regulator of the transcriptional response to hypoxia; however, little is known 
about the impact of hypercapnia on gene transcription. Because of the 
relationship between hypoxia and hypercapnia, we investigated the effect of 
hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability 
and HIF target gene expression both in mice and cultured cells in a manner that 
was at least in part independent of the canonical O2-dependent HIF degradation 
pathway. The suppressive effects of hypercapnia on HIF-α protein stability could 
be mimicked by reducing intracellular pH at a constant level of partial pressure 
of CO2 Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase that 
blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α 
protein. Based on these results, we hypothesize that hypercapnia 
counter-regulates activation of the HIF pathway by reducing intracellular pH and 
promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may 
play a key role in the pathophysiology of diseases where HIF is implicated.