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


Type
Article
Change log
Authors
Bailey, Peter SJ 
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.

Description
Keywords
2-HG, 2-OG dependent dioxygenase, 2-hydroxyglutarate, HIF, PHD, TCA cycle, hypoxia inducible factors, iron metabolism, prolyl hydroxylase
Journal Title
Biomedicines
Conference Name
Journal ISSN
2227-9059
2227-9059
Volume Title
6
Publisher
MDPI AG
Sponsorship
Wellcome Trust (102770/Z/13/Z)
Lister Institute of Preventive Medicine (unknown)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (205252/Z/16/Z)