Peroxynitrite as an alternative donor of oxygen in HIF-1α proline hydroxylation under low oxygen availability

In the last years, nitric oxide (NO) mediated signaling became an integral component in understanding physiological and pathophysiological processes of cell proliferation, death or cellular adaptation. Among other activities, NO affects multiple targets that allow regulation of gene expression. Recently, NO was found to attenuate accumulation of hypoxia inducible factor-1alpha (HIF-1 alpha) under hypoxic conditions because of several mechanisms: redistribution of oxygen toward nonrespiratory oxygen-dependent targets (like HIF-1 alpha proline hydroxylases-PHDs, which perform hydroxylation of Pro402/564 of HIF-1 alpha leading to its proteasomal degradation); in addition, peroxynitrite formed during interactions between NO and mitochondria derived superoxide leads to an increase in cytosolic iron/2-oxoglutarate (2-OG), which required for PHD activation. Here, we propose a hypothesis that peroxynitrite, formed in the cells upon exposure to NO under low oxygen availability, serves as an alternative donor of oxygen for activated PHDs so they can perform HIF-1 alpha proline hydroxylation to de-accumulate the protein.