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Abstract
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a commonly pervasive inherited disease in many parts of the world. The complete lack of G6PD activity in a mouse model causes embryonic lethality. The G6PD-deficient Caenorhabditis elegans model also shows embryonic death as indicated by a severe hatching defect. Although increased oxidative stress has been implicated in both cases as the underlying cause, the exact mechanism has not been clearly delineated. In this study with C. elegans, membrane-associated defects, including enhanced permeability, defective polarity and cytokinesis, were found in G6PD-deficient embryos. The membrane-associated abnormalities were accompanied by impaired eggshell structure as evidenced by a transmission electron microscopic study. Such loss of membrane structural integrity was associated with abnormal lipid composition as lipidomic analysis revealed that lysoglycerophospholipids were significantly increased in G6PD-deficient embryos. Abnormal glycerophospholipid metabolism leading to defective embryonic development could be attributed to the increased activity of calcium-independent phospholipase A2 (iPLA) in G6PD-deficient embryos. This notion is further supported by the fact that the suppression of multiple iPLAs by genetic manipulation partially rescued the embryonic defects in G6PD-deficient embryos. In addition, G6PD deficiency induced disruption of redox balance as manifested by diminished NADPH and elevated lipid peroxidation in embryos. Taken together, disrupted lipid metabolism due to abnormal redox homeostasis is a major factor contributing to abnormal embryonic development in G6PD-deficient C. elegans.
Highlights
The housekeeping gene glucose-6-phosphate dehydrogenase (G6PD), which is ubiquitously present in prokaryotic and eukaryotic organisms, encodes the rate-limiting enzyme in the pentose phosphate pathway
Abnormal membrane function of embryos from G6PDdeficient C. elegans Defective permeability of G6PD RNAi knockdown (Gi) embryos: Previously, we have established the G6PDdeficient C. elegans model by feeding wild-type C. elegans with Escherichia coli expressing RNA-mediated interference (RNAi) targeting G6PD gene[7] and most embryos derived from G6PD-deficient C. elegans failed to hatch.[7]
There was no significant difference (P40.05) in the transcriptional level of independent phospholipase A2 (iPLA) in the adult, gonad or embryo between Mock and G6PD-deficient C. elegans, indicating that G6PD deficiency stimulated iPLA protein activity. These results demonstrate that the iPLA activity was greatly enhanced in G6PD-deficient embryos and was consistent with the lipidomic data that lysoglycerophospholipids were dramatically altered in G6PD-deficient embryos (Figure 3c)
Summary
The housekeeping gene glucose-6-phosphate dehydrogenase (G6PD), which is ubiquitously present in prokaryotic and eukaryotic organisms, encodes the rate-limiting enzyme in the pentose phosphate pathway. Embryonic cell death induced by G6PD deficiency has been attributed to increased oxidative stress. G6PD-deficient embryonic stem cells fail to survive during oxidative stress.[8,9,10] G6PD-knockout mice show embryonic arrest and death which is caused by oxidative damage.[5] G6PD-. NADPH is required for reductive biosynthesis, such as fatty acid synthesis and modification, during embryogenesis.[12,13] Lipids are essential in embryogenesis, and for example, perturbation in the regulation of membrane lipid metabolism causes early embryonic lethality in mouse.[14,15] How altered oxidative stress may affect lipid metabolism has largely been overlooked during embryonic development in G6PD-deficient organisms
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