Abstract
The fruitfly Drosophila melanogaster offers promise as a genetically tractable model for studying adaptation to hypoxia at the cellular level, but the metabolic basis for extreme hypoxia tolerance in flies is not well known. Using 1H NMR spectroscopy, metabolomic profiles were collected under hypoxia. Accumulation of lactate, alanine, and acetate suggested that these are the major end products of anaerobic metabolism in the fly. A constraint-based model of ATP-producing pathways was built using the annotated genome, existing models, and the literature. Multiple redundant pathways for producing acetate and alanine were added and simulations were run in order to find a single optimal strategy for producing each end product. System-wide adaptation to hypoxia was then investigated in silico using the refined model. Simulations supported the hypothesis that the ability to flexibly convert pyruvate to these three by-products might convey hypoxia tolerance by improving the ATP/H+ ratio and efficiency of glucose utilization.
Highlights
Understanding cellular adaptation to hypoxia is central to the design of treatments for injury caused by ischemia–reperfusion, stroke, and myocardial infarction
Cell damage during acute hypoxia is thought to be caused by imbalances such as decreased pH, altered calcium homeostasis, increased intracellular osmotic pressure, and mitochondrial damage, resulting directly and indirectly from decreased ATP (Hochachka and Somero, 2002; Corbucci et al, 2005)
At the cellular level, hypoxia resistance mechanisms most likely evolved very early and appear to be highly conserved among species (O’Farrell, 2001). Lending support to this hypothesis, several genes have been discovered in the fruitfly Drosophila melanogaster that are similar in sequence and function to human genes for regulation of metabolism, signaling, and transcription during hypoxia (Piacentini and Karliner, 1999; Wingrove and O’Farrell, 1999; Lavista-Llanos et al, 2002; Pan and Hardie, 2002)
Summary
Understanding cellular adaptation to hypoxia is central to the design of treatments for injury caused by ischemia–reperfusion, stroke, and myocardial infarction. At the cellular level, hypoxia resistance mechanisms most likely evolved very early and appear to be highly conserved among species (O’Farrell, 2001) Lending support to this hypothesis, several genes have been discovered in the fruitfly Drosophila melanogaster that are similar in sequence and function to human genes for regulation of metabolism, signaling, and transcription during hypoxia (Piacentini and Karliner, 1999; Wingrove and O’Farrell, 1999; Lavista-Llanos et al, 2002; Pan and Hardie, 2002). Differences in anaerobic generation of ATP are likely to be part of the reason for the disparity in hypoxia tolerance between humans and flies; Drosophila anaerobic metabolism is not well known. Simulations were compared with those of classical anaerobic energy pathways in mammals to generate hypotheses for mechanisms of hypoxia tolerance in flies
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