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Biomedicines 2018, 6(2), 60; https://doi.org/10.3390/biomedicines6020060

Metabolic Regulation of Hypoxia-Inducible Transcription Factors: The Role of Small Molecule Metabolites and Iron

Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, UK
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Received: 24 April 2018 / Revised: 11 May 2018 / Accepted: 15 May 2018 / Published: 17 May 2018
(This article belongs to the Special Issue Hypoxia)
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Abstract

Hypoxia-inducible transcription factors (HIFs) facilitate cellular adaptations to low-oxygen environments. However, it is increasingly recognised that HIFs may be activated in response to metabolic stimuli, even when oxygen is present. Understanding the mechanisms for the crosstalk that exists between HIF signalling and metabolic pathways is therefore important. This review focuses on the metabolic regulation of HIFs by small molecule metabolites and iron, highlighting the latest studies that explore how tricarboxylic acid (TCA) cycle intermediates, 2-hydroxyglutarate (2-HG) and intracellular iron levels influence the HIF response through modulating the activity of prolyl hydroxylases (PHDs). We also discuss the relevance of these metabolic pathways in physiological and disease contexts. Lastly, as PHDs are members of a large family of 2-oxoglutarate (2-OG) dependent dioxygenases that can all respond to metabolic stimuli, we explore the broader role of TCA cycle metabolites and 2-HG in the regulation of 2-OG dependent dioxygenases, focusing on the enzymes involved in chromatin remodelling. View Full-Text
Keywords: hypoxia inducible factors; HIF; prolyl hydroxylase; PHD; 2-OG dependent dioxygenase; 2-hydroxyglutarate; 2-HG; iron metabolism; TCA cycle hypoxia inducible factors; HIF; prolyl hydroxylase; PHD; 2-OG dependent dioxygenase; 2-hydroxyglutarate; 2-HG; iron metabolism; TCA cycle
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Bailey, P.S.J.; Nathan, J.A. Metabolic Regulation of Hypoxia-Inducible Transcription Factors: The Role of Small Molecule Metabolites and Iron. Biomedicines 2018, 6, 60.

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