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.
Highlights
Hypoxia-Inducible transcription Factors (HIFs) underpin metazoan cellular responses to oxygen availability [1,2,3,4,5], coordinating transcriptional changes that allow cells to adapt to hypoxic environments
Our gene-trap mutagenesis approach identified that mutations in lipoic acid synthase (LIAS) leads to decreased oxoglutarate dehydrogenase complex (OGDHc), formation, prolyl hydroxylases (PHDs) inhibition and HIF-1α stabilisation [55]
The full biological implications for the regulation of PHD activity by lipoylation remain to be determined, but it is possible that HIF activation in the variant-form of Leigh syndrome may function as a survival mechanism to counteract the impaired mitochondrial function due to LIAS loss
Summary
Hypoxia-Inducible transcription Factors (HIFs) underpin metazoan cellular responses to oxygen availability [1,2,3,4,5], coordinating transcriptional changes that allow cells to adapt to hypoxic environments. HIFs may be activated independently of oxygen through a multitude of mechanisms, including mitochondrial function, changes in intracellular metabolites or iron availability, reactive oxygen species (ROS) generation, and modulation of the mammalian target of rapamycin (mTOR) pathway. The HIF-1α and HIF-2α subunits are rapidly degraded by proteasomes [6,7], preventing the formation of the dimeric HIF complex (the role of HIF3α in the HIF response remains unclear). Key to this rapid degradation are the Prolyl Hydroxylase Domain containing enzymes (PHDs, known as EGLNs), which act as oxygen sensors. We discuss the interplay between this metabolic regulation of HIFs and other 2-OG-dependent dioxygenases in cell fate decisions, and how exploring the pathways involved may present new opportunities to intervene therapeutically in HIF-dependent disease processes
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