HIF expression or stabilization has many effects on cell metabolism, both directly and indirectly. Under normoxic conditions, HIF1α and HIF2α (HIFα) are hydroxylated by PHDs (and FIH) using available oxygen and α-ketoglutarate, which leads to proteosomal degradation. When oxygen tension is low, HIFα translocates to the nucleus, where it binds to DNA with its heterodimeric binding partner HIFβ to initiate transcription of HIF target genes. These transcription products affect all levels of cellular metabolism to reduce oxidative phosphorylation (OXPHOS) in mitochondria and favor glycolysis, from substrate transport to apoptotic signaling molecules (e.g., BNIP3). Some evidence suggests that HIFα may also directly modulate mitochondrial metabolism, through a currently undefined mechanism. Metabolite levels are independently affected by changes in oxygen tension and HIF expression through reduction of PHD activity, which influences concentrations of several citric acid metabolites (e.g., α-ketoglutarate and succinate). Dashed lines indicate transport across the mitochondrial membrane, where these metabolites serve distinct roles in each location. PPP, pentose phosphate pathway.