Oxygen-dependent regulation of antioxidant production by HIF1. Under hypoxic conditions, HIFs activate the transcription of PHGDH, PSAT1, and PSPH (red) to increase conversion of glucose to serine (serine synthesis pathway); and SHMT2, MTHFD2, and MTHFD1L (blue) to increase generation of mitochondrial NADPH (mitochondrial one-carbon metabolism), which is required to convert glutathione from oxidized (GSSG) to reduced (GSH) form to protect against increased ROS generated by the ETC. Genes encoding proteins that generate cytosolic NADPH are either not consistently induced [SHMT1, MTHFD1 (purple)] or actively repressed [G6PD (green)] under hypoxic conditions. G6PD, glucose-6-phosphate dehydrogenase; MTHFD, methylene tetrahydrofolate dehydrogenase; MTHFD1L, MTHFD1-like; PHGDH, phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; SHMT, serine hydroxymethyltransferase.