Abstract
Hypoxia-induced cell injury has been related to multiple pathological conditions. In order to render hypoxia-sensitive cells and tissues resistant to low O2 environment, in this current study, we used Drosophila melanogaster as a model to dissect the mechanisms underlying hypoxia-tolerance. A D. melanogaster strain that lives perpetually in an extremely low-oxygen environment (4% O2, an oxygen level that is equivalent to that over about 4,000 m above Mt. Everest) was generated through laboratory selection pressure using a continuing reduction of O2 over many generations. This phenotype is genetically stable since selected flies, after several generations in room air, survive at this low O2 level. Gene expression profiling showed striking differences between tolerant and naïve flies, in larvae and adults, both quantitatively and qualitatively. Up-regulated genes in the tolerant flies included signal transduction pathways (e.g., Notch and Toll/Imd pathways), but metabolic genes were remarkably down-regulated in the larvae. Furthermore, a different allelic frequency and enzymatic activity of the triose phosphate isomerase (TPI) was present in the tolerant versus naïve flies. The transcriptional suppressor, hairy, was up-regulated in the microarrays and its binding elements were present in the regulatory region of the specifically down-regulated metabolic genes but not others, and mutations in hairy significantly reduced hypoxia tolerance. We conclude that, the hypoxia-selected flies: (a) altered their gene expression and genetic code, and (b) coordinated their metabolic suppression, especially during development, with hairy acting as a metabolic switch, thus playing a crucial role in hypoxia-tolerance.
Highlights
Mammalian tissues experience a reduction in oxygen delivery at high altitude or during certain disease states, such as myocardial infarction and stroke
Hypoxia-induced injury has been related to multiple pathological conditions
Several adaptive changes were identified in the hypoxia-selected flies that included up-regulation of multiple signal transduction pathways, modulation of cellular respiration enzymes, and polymorphic differences in metabolic enzymes
Summary
Mammalian tissues experience a reduction in oxygen delivery at high altitude or during certain disease states, such as myocardial infarction and stroke. Cells, tissues and organisms have developed various strategies to adapt to such O2 limited condition. Turtle neurons are very tolerant to low oxygen and can survive without O2 for hours and days [1,2]. Mammalian neurons are very sensitive to reduced oxygen and cannot survive for even minutes under similar conditions. It has been demonstrated that a number of hypoxia-tolerant animals (e.g. Pseudemys scripta and Crucian Carp) reduce their O2 consumption during hypoxia in such a way to minimize the mismatch between O2 supply and demand [3,4,5]. We do not have an adequate understanding of the mechanisms that are responsible for reducing metabolic rate during low O2 conditions; and the mechanisms that are responsible for coordinating the suppression of these metabolic processes are still largely unknown
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