Systems biology analysis using a genome-scale metabolic model shows that phosphine triggers global metabolic suppression in a resistant strain of C. elegans

148 words < 350 words) Background: Pest insects are increasingly resistant to phosphine gas, which is used globally to protect grain reserves. The enzyme dihydrolipoamide dehydrogenase (DLD) is a phosphine resistance factor and participates in four key steps of core metabolism, making it a potential central metabolic regulator. Results: Here we used microarray data and NMR-based metabolomics to characterize the phosphine response of wild-type C. elegans and the phosphine-resistant strain dld1(wr4) which has a partial loss-of-function mutation in the gene for DLD. In addition, we have constructed CeCon, a C. elegans genome-scale metabolic model to facilitate integration of gene expression and metabolomics data. Conclusions: The resulting systems biology analysis is consistent with the hypothesis that adaptation to a hypometabolic state is the most prominent mechanism of phosphine resistance in this nematode strain. The involvement of DLD in regulating and creating hypometabolic adaptation has implications for other biological phenomena involving hypometabolism, such as reperfusion injury and metabolic resistance.