Year: 2009
Type: article
Abstract: BACKGROUND: Cellular hypoxia is a component of many diseases, but mechanisms of global hypoxic adaptation and resistance are not completely understood. Previously, a population of Drosophila flies was experimentally selected over several generations to survive a chronically hypoxic environment. NMR-based metabolomics, combined with flux-balance simulations of genome-scale metabolic networks, can generate specific hypotheses for global reaction fluxes within the cell. We applied these techniques to compare metabolic activity during acute hypoxia in muscle tissue of adapted versus "naïve" control flies. RESULTS: Metabolic profiles were gathered for adapted and control flies after exposure to acute hypoxia using 1H NMR spectroscopy. Principal Component Analysis suggested that the adapted flies are tuned to survive a specific oxygen level. Adapted flies better tolerate acute hypoxic stress, and we explored the mechanisms of this tolerance using a flux-balance model of central metabolism. In the model, adapted flies produced more ATP per glucose and created fewer protons than control flies, had lower pyruvate carboxylase flux, and had greater usage of Complex I over Complex II. CONCLUSION: We suggest a network-level hypothesis of metabolic regulation in hypoxia-adapted flies, in which lower baseline rates of biosynthesis in adapted flies draws less anaplerotic flux, resulting in lower rates of glycolysis, less acidosis, and more efficient use of substrate during acute hypoxic stress. In addition we suggest new specific hypothesis, which were found to be consistent with existing data.
Source: BMC Systems Biology
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,290
Funders: National Science Foundation, American Heart Association, National Institutes of Health, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1000054730, G1058586922, Molecular basis of cell tolerance to 02 deprivation, The control landscape of selective cell death, Molecular Algorithmics for Pharmacological Interventions, NATIONAL BIOMEDICAL COMPUTATION RESOURCE, Hypoxia in Development; Injury and Adaptation Mechanisms, G844224737, MSM: Multi-scale modeling of the mouse heart: from genotype to phenotype
OpenAlex ID: W2118917780