Fig. 2

NAD and hypoxic metabolism. Inflammation, reactive oxygen species, and/or hypoxia promote the stabilization of hypoxia-inducible transcription factor (HIF)-1α. A dimer, composed of HIF-1α and HIF-1β, activates glycolytic genes, including SLC2A1/GLUT1 (glucose transporter), HK2 (hexokinase 2), ALDOA (aldolase), PGK1 (phosphoglycerate kinase-1), ENOL (enolase), LDHA (lactate dehydrogenase A), and PDK1 (pyruvate dehydrogenase kinase 1). These gene products redirect pyruvate catabolism in the mitochondria to the production of lactate. Further, the HIF-1α:HIF-1β heterodimer inhibits the transcription of fatty acid genes associated with β-oxidation. CPT1A (carnitine palmitoyltransferase 1A) catalyzes the transfer of acyl groups into the mitochondria. PPARA (peroxisome proliferator activated receptor alpha) is a cofactor to PGC-1 α (Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha) in mitochondrial biogenesis. Redox reactions involving oxidized NAD (nicotinamide adenine dinucleotide) or FAD (flavin adenine dinucleotide) and their reduced forms (NADH, FADH) promote each form of metabolism, resulting in the production of ATP (adenosine triphosphate) from ADP (adenosine diphosphate) and Pi (inorganic phosphate). Acetyl-CoA, formed from glycolysis or β -oxidation, fuels the citric acid cycle and the electron transport chain. NAD reduction reactions are important for α-ketoglutarate production, which is also formed through glutaminolysis and the production of glutamate. Iron, oxygen, ascorbate, and α-ketoglutarate support the activation of prolyl-hydroxylase (PHD)-2, which adds hydroxyl groups to HIF-1α and promotes HIF-1α binding to the von Hippel-Lindau (VHL) E3 ubiquitin ligase. VHL adds ubiquitin to HIF-1α, targeting HIF-1α for degradation by the proteasome.