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Flexibility in energy metabolism supports hypoxia tolerance in Drosophila flight muscle: metabolomic and computational systems analysis

Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
Molecular Systems Biology (Impact Factor: 14.1). 02/2007; 3:99. DOI: 10.1038/msb4100139
Source: PubMed

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 (1)H 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.

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    • "To reduce the accumulation of pyruvate, it can be transformed into acetylpyruvate using acetate (in addition to the transformation into lactate and alanine mentioned above). Although these specific end products were not known for D. cephalotes, they corroborate previous research on responses to hypoxia in Drosophila (Feala et al. 2007) and correspond to known by-products of anaerobic metabolism in other terrestrial insects (Hoback and Stanley 2001). Insects typically rely on the glycerol-3- phosphate shuttle to regenerate NADþ, which is important for maintaining glycolysis (Gilmour 1961), thus explaining the higher levels of glycerol and glyc- erol-3-phosphate. "
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    ABSTRACT: Thermal limits in ectotherms may arise through a mismatch between supply and demand of oxygen. At higher temperatures, the ability of their cardiac and ventilatory activities to supply oxygen becomes insufficient to meet their elevated oxygen demand. Consequently, higher levels of oxygen in the environment are predicted to enhance tolerance of heat, whereas reductions in oxygen are expected to reduce thermal limits. Here, we extend previous research on thermal limits and oxygen limitation in aquatic insect larvae and directly test the hypothesis of increased anaerobic metabolism and lower energy status at thermal extremes. We quantified metabolite profiles in stonefly nymphs under varying temperatures and oxygen levels. Under normoxia, the concept of oxygen limitation applies to the insects studied. Shifts in the metabolome of heat-stressed stonefly nymphs clearly indicate the onset of anaerobic metabolism (e.g., accumulation of lactate, acetate, and alanine), a perturbation of the tricarboxylic acid cycle (e.g., accumulation of succinate and malate), and a decrease in energy status (e.g., ATP), with corresponding decreases in their ability to survive heat stress. These shifts were more pronounced under hypoxic conditions, and negated by hyperoxia, which also improved heat tolerance. Perturbations of metabolic pathways in response to either heat stress or hypoxia were found to be somewhat similar but not identical. Under hypoxia, energy status was greatly compromised at thermal extremes, but energy shortage and anaerobic metabolism could not be conclusively identified as the sole cause underlying thermal limits under hyperoxia. Metabolomics proved useful for suggesting a range of possible mechanisms to explore in future investigations, such as the involvement of leaking membranes or free radicals. In doing so, metabolomics provided a more complete picture of changes in metabolism under hypoxia and heat stress.
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    • "Provided that the fruit fly's MR has a Q 10 of 2.2 (Schilman et al., 2011), temperature is expected to affect damage and recovery rates during anoxia and reperfusion. In the course of anoxia, low temperature probably decreases the build-up of anaerobic metabolites, like alanine, acetate and lactate (Feala et al., 2007), and possibly delays the consumption of endogenous antioxidant enzymes and energy metabolites (Zhang et al., 2011). When O 2 supply is restored, hypothermia could also reduce the build-up of reactive oxygen/nitrogen species (ROS/RNS) and slow down recovery and repair processes (e.g. "
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    Journal of Experimental Biology 08/2012; 215(23). DOI:10.1242/jeb.074468 · 3.00 Impact Factor
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    • "Higher body temperatures will increase metabolic rates of ectotherms, probably leading to increased production rates of anaerobic end-products and ROS during re-exposure to O 2 . Higher metabolic rates will increase the rate of formation of anaerobic endproducts: lactate, alanine and acetate in Drosophila (Feala et al., 2007). Higher temperatures probably also increase ion leakages that disrupt membrane electrical function. "
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