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Review
. 2013 Sep:62:26-36.
doi: 10.1016/j.freeradbiomed.2013.01.026. Epub 2013 Jan 31.

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

Rachel E Speer  1 , Saravanan S Karuppagounder  2 , Manuela Basso  2 , Sama F Sleiman  2 , Amit Kumar  2 , David Brand  2 , Natalya Smirnova  2 , Irina Gazaryan  2 , Soah J Khim  2 , Rajiv R Ratan  3
Affiliations
Review

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

Rachel E Speer et al. Free Radic Biol Med. 2013 Sep.

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.

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Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

Figure 1
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.
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References

    1. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B, 3rd, Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–1072. - PMC - PubMed
    1. Ryu H, Lee J, Zaman K, Kubilis J, Ferrante RJ, Ross BD, Neve R, Ratan RR. Sp1 and Sp3 are oxidative stress-inducible, antideath transcription factors in cortical neurons. J Neurosci. 2003;23:3597–3606. - PMC - PubMed
    1. Lange PS, Chavez JC, Pinto JT, Coppola G, Sun CW, Townes TM, Geschwind DH, Ratan RR. ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J Exp Med. 2008;205:1227–1242. - PMC - PubMed
    1. Ryu H, Lee J, Olofsson BA, Mwidau A, Dedeoglu A, Escudero M, Flemington E, Azizkhan-Clifford J, Ferrante RJ, Ratan RR. Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc Natl Acad Sci U S A. 2003;100:4281–4286. - PMC - PubMed
    1. Siddiq A, Ayoub IA, Chavez JC, Aminova L, Shah S, LaManna JC, Patton SM, Connor JR, Cherny RA, Volitakis I, Bush AI, Langsetmo I, Seeley T, Gunzler V, Ratan RR. Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J Biol Chem. 2005;280:41732–41743. - PMC - PubMed

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