Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning

Abstract

Hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to reduced oxygen availability by regulating gene expression. A critical cell-autonomous adaptive response to chronic hypoxia controlled by HIF-1 is reduced mitochondrial mass and/or metabolism. Exposure of HIF-1-deficient fibroblasts to chronic hypoxia results in cell death due to excessive levels of reactive oxygen species (ROS). HIF-1 reduces ROS production under hypoxic conditions by multiple mechanisms including: a subunit switch in cytochrome c oxidase from the COX4-1 to COX4-2 regulatory subunit that increases the efficiency of complex IV; induction of pyruvate dehydrogenase kinase 1, which shunts pyruvate away from the mitochondria; induction of BNIP3, which triggers mitochondrial selective autophagy; and induction of microRNA-210, which blocks assembly of Fe/S clusters that are required for oxidative phosphorylation. HIF-1 is also required for ischemic preconditioning and this effect may be due in part to its induction of CD73, the enzyme that produces adenosine. HIF-1-dependent regulation of mitochondrial metabolism may also contribute to the protective effects of ischemic preconditioning. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.

Fig. 1

Mechanisms by which HIF-1 regulates gene expression. (A) Top: HIF-1 binds directly to target genes at a cis-acting hypoxia response element (HRE) and recruits coactivator proteins such as p300 to increase gene transcription. The coding sequence (CDS) of these HIF-1 target genes encode proteins that mediate adaptive responses to hypoxia. Bottom: There are only several rare examples in which HIF-1 binding leads to transcriptional repression. (B) HIF-1 binds directly to and transactivates a gene that encodes a transcription factor (TF), which either activates (TF_A) or represses (TF_B) the expression of secondary target genes by binding to its cognate transcription factor binding site (TFBS). (C) HIF-1 activates the transcription of genes encoding proteins with histone demethylase (HDM) activity. Demethylation of histones alters chromatin structure, which either decreases (as illustrated) or increases the expression of genes within the modified chromatin. (D) HIF-1 activates transcription of genes encoding microRNAs that bind to mRNAs and either block their translation or induce their degradation. (E) HIF-1a binds to the transcription factor SP1 and blocks activation of the gene encoding the mismatch DNA repair protein MSH2, thereby functioning as a co-repressor. (F) HIF-1a binds to the Notch intracellular domain (NICD) and potentiates transcriptional activation of Notch target genes, thereby functioning as a co-activator. (Adapted from ref. .)

Fig. 2

Negative regulation of HIF-1 activity by oxygen. Top: In the presence of O₂: prolyl hydroxylation of HIF-1a leads to binding of the von Hippel-Lindau protein (VHL), which recruits a ubiquitin protein-ligase that targets HIF-1a for proteasomal degradation; and asparaginyl hydroxylation of HIF-1a blocks the binding of the coactivator protein p300. Bottom: Under hypoxic conditions, the hydroxylation reactions are inhibited, leading to decreased VHL binding and protein stabilization as well as increased p300 binding and transcriptional activation.

Fig. 3

Regulation of mitochondrial metabolism by HIF-1. Acute hypoxia leads to increased mitochondrial generation of reactive oxygen species (ROS). Decreased O₂ and increased ROS levels lead to decreased HIF-1a hydroxylation (see Fig. 2) and increased HIF-1-dependent transcription of genes encoding proteins (LDHA, PDK1, BNIP3, COX4-2, LON) or microRNA (miR-210) that reduce mitochondrial respiration and ROS production.