2017 SfRBM Discovery Award Lecture Maintenance Of Oxygen And Redox Homeostasis By Hypoxia-Inducible Factor 1

Abstract

In virtually every metazoan species, cells express the transcriptional activator hypoxia-inducible factor 1 (HIF-1) in response to decreased O2 availability. HIF-1 activates the transcription of a large battery of target genes, many of which encode proteins that serve either to increase O2 delivery or to decrease O2 consumption. The latter is likely to represent a primordial function of HIF-1, which is expressed even in animals with bodies that are too simple to require specialized systems for O2 delivery. Studies performed with mouse embryo fibroblasts revealed coordinate, HIF-1-dependent activation of genes that inhibit respiration and stimulate glycolysis. This metabolic reprogramming is required to maintain redox homeostasis: HIF-1-deficient fibroblasts exposed to chronic hypoxia do not switch from respiration to glycolysis and die due to ROS toxicity. More recently, analysis of human breast cancer cells has revealed that hypoxia induces coordinate, HIF-1-dependent transcriptional activation of genes encoding enzymes of the serine synthesis pathway and one-carbon metabolism that increase mitochondrial NADPH production, which is required to detoxify ROS produced under hypoxic conditions. Failure to do so leads to increased cell death and impairs the enrichment of breast cancer stem cells that otherwise occurs in response to hypoxia. Thus, HIF-1 controls both the production and detoxification of ROS under conditions of chronic hypoxia. Different cell types use different strategies to modulate metabolism in order to maintain redox homeostasis under hypoxic conditions. These studies have led to major paradigm shifts in our understanding of oxygen homeostasis: (i) ROS levels do not increase monotonically with increasing pO2; rather, mitochondrial function is optimized for physiological pO2 and any increase or decrease in O2 availability leads to increased ROS levels; and (ii) the switch from oxidative to glycolytic metabolism does not occur in order to maintain energy homeostasis, but rather to maintain redox homeostasis under hypoxic conditions.