Hypoxia-inducible factor prolyl hydroxylases as targets for neuroprotection by "antioxidant" metal chelators: From ferroptosis to stroke

Abstract

Neurologic conditions including stroke, Alzheimer disease, Parkinson disease, and Huntington disease are leading causes of death and long-term disability in the United States, and efforts to develop novel therapeutics for these conditions have historically had poor success in translating from bench to bedside. Hypoxia-inducible factor (HIF)-1α mediates a broad, evolutionarily conserved, endogenous adaptive program to hypoxia, and manipulation of components of the HIF pathway is neuroprotective in a number of human neurological diseases and experimental models. In this review, we discuss molecular components of one aspect of hypoxic adaptation in detail and provide perspective on which targets within this pathway seem to be ripest for preventing and repairing neurodegeneration. Further, we highlight the role of HIF prolyl hydroxylases as emerging targets for the salutary effects of metal chelators on ferroptosis in vitro as well in animal models of neurological diseases.

Keywords: Free radicals; Hypoxia-inducible factors; Metal chelators; Neurodegeneration; Prolyl hydroxylases; Transcription.

Figure 1. Schematic of oxygen-dependent HIF-1α regulation

A. Under normoxic conditions, PHDs hydroxylate P564 on HIF-1α, allowing it to be recognized by the E3 ubiquitin ligase von Hippel-Lindau protein (VHL), ubiquitinated, and targeted for proteasomal degradation. As members of a large family of iron- and 2-oxoglutarate dependent dioxygenases, PHDs integrate multiple signals of metabolic homeostasis, and are one of many such sensors; further, PHDs have HIF-independent substrates, and HIF protein levels and transcriptional activity are regulated in many PHD-independent ways. B. Under hypoxia, PHDs are inhibited, allowing HIF-1α to elude degradation, dimerize with its β partner in the nucleus, bind transcriptional coactivators and hypoxia response elements in promoter regions of target genes, and enhance transcription rates. Glucose deprivation has been reported to decrease hypoxic stabilization of HIF-1α; the mechanisms by which this occurs are unclear.