Metabolic Adaptation to Chronic Hypoxia: Lessons from Drosophila Model

Hypoxia-induced cell injury has been related to multiple pathological conditions. Metabolic adaptation plays a critical role in hypoxia adaptation to protect cells and tissues from hypoxia-induced injuries. However, mechanisms underlying metabolic adaptation and hypoxia tolerance are largely unknown. To dissect such mechanisms, we generated a Drosophila melanogaster population that lives perpetually in an extremely low-oxygen environment (i.e., 4% O2, an oxygen level that is equivalent to that over ~4,000 m above Mt. Everest) through long-term laboratory selection. Expression profiling and NMR-based metabolomics were used to determine the changes in gene expression and metabolic activities in the hypoxia-adapted flies. Gene expression profiling showed striking quantitative and qualitative differences between adapted and naïve flies. We found a synchronized up-regulation of genes encoding protein components of several signal transduction pathways, including Notch and Toll/Imd pathways, in the hypoxia-adapted flies. In contrast, a coordinated down-regulation was found in a majority of metabolic genes. Using a combination of bioinformatic and genetic tools, we discovered that the binding element of transcriptional suppressor, hairy, which was up-regulated in the hypoxia-adapted flies, is a metabolic switch and regulates hypoxia-tolerance by down-regulating the expression of genes encoding TCA cycle enzymes. Furthermore, NMR-based metabolomics, combined with flux-balance simulations of genome-scale metabolic networks, was used to compare metabolic activity during acute hypoxia in muscle tissue of adapted versus naïve control flies. We conclude that the hypoxia-selected flies altered their gene expression and metabolic activity and coordinated their metabolic suppression with hairy acting as a metabolic switch. These adaptive mechanisms identified in the hypoxia-adapted Drosophila model may also play a crucial role in protecting hypoxia-induced injuries in mammals.