Fig. 9

 A schematic showing how sensing by the redox couple NAD⁺/NADH acetylation mediates HIF-1α degradation and stabilization, employing SIRT1 during acute and chronic hypoxia. During normoxia, oxygen-sensing HIF-1α prolines, Pro402 and Pro564, are hydroxylated by HIF hydroxylases, promoting HIF-1α degradation in an oxygen-sensitive manner. HIF-1α degradation occurred during chronic hypoxia, however, is controlled in an NADH-sensitive manner via acetylation of the protein. NADH, the level of which is upregulated during chronic hypoxia, functions as a destabilizing messenger for chronic HIF-1α decay. Surplus NADH inactivates SIRT1 (iSIRT1), and HIF-1α interaction with VHL that is attenuated after commencement of hypoxia is thus renewed. This leads to elevated ubiquitination and degradation of HIF-1α. However, during the acute phase of hypoxia, NAD⁺ functions as a stabilizing messenger; the NAD⁺-sensing protein SIRT1 (aSIRT1) protects HIF-1α from redox-sensitive acetylation, thereby facilitating dissociation of HIF-1α from VHL and initiating HIF-1α stabilization