Isocitrate dehydrogenase‐1 deficiency exacerbates growth defects and metabolic alteration in Caenorhabditiselegans induced by glucose 6‐phosphate dehydrogenase deficiency

Abstract

NADPH is a key reducing equivalent that maintains redox homeostasis and supports reductive biosynthesis. Lack of major NADPH producing enzymes predisposes cells to growth retardation and demise. Inactivation of the NADPH generating enzymes, glucose 6‐phosphate dehydrogenase (G6PD), the rate limiting enzyme of the pentose phosphate pathway, and isocitrate dehydrogenase (IDH) has been hypothesized to affect growth and development in the nematode, C. elegans. Toward this end, the G6PD/IDH1 double‐deficient C. elegans model was shown to display shrinkage of body size, growth retardation, slow locomotion and impaired molting. Global metabolomic analysis was employed to address whether or not metabolic pathways were altered by NADPH depletion by the G6PD/IDH1 double‐deficiency. Principal component analysis (PCA) points to a distinct metabolomic profile of G6PD/IDH1 doubledeficiency. Further metabolomic analysis revealed that NADPH‐dependent and glutamate‐dependent amino acid biosynthesis were significantly impaired. Consequently, the reduction in amino acids may affect protein synthesis, as indicated by the absence of NAS‐37 expression during the molting process. All in all, these findings support the notion that inactivation of G6PD and IDH1 causes growth retardation and molting defects, possibly mediated by impaired amino acid biosynthesis and metabolism in C. elegans.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.