LAUSR

NADPH plays an indispensable role in normal cellular physiology by maintaining redox homeostasis and providing reducing power for reductive biosynthesis. Isocitrate dehydrogenase-1 (IDH1) and glucose 6-phosphate dehydrogenase (G6PD) are the two major NADPH-generating enzymes in cells. Dysfunction of NADPH-generating enzyme results redox imbalance leading to abnormal cellular function and growth retardation. A severe redox imbalance model: G6PD/IDH1 double deficient C. elegans was generated to delineate the importance of redox homeostasis during larval development. The small body size, growth retardation and molting defects were observed in G6PD/IDH1 double-deficient C. elegans, but not in controls including either G6PD or IDH1 deficient C. elegans. The global metabolomics analyses were utilized to assess the effects of severe redox imbalance in metabolic pathways. Principal component analysis (PCA) showed that a distinct pattern of metabolic profile was found in G6PD/IDH1 double-deficient C. elegans as compared to controls. The metabolomic pathway analysis indicated that many of amino acid biosynthetic pathways were altered, especially in those amino acids requiring NADPH for their synthesis. The decreased expression of molting protease NAS-37 during molting in C. elegans might reflect the effects of reduced amino acid level in protein synthesis. Furthermore, the level of MDA and 4-HNE, which are lipid peroxidation markers, were increased in G6PD/IDH1 double-deficient C. elegans. Taken together, these results suggest that G6PD and IDH1 are important to maintain redox homeostasis for normal cellular and physiologic functions.