title: Impaired embryonic development in glucose-6-phosphate dehydrogenase-deficient Caenorhabditis elegans due to abnormal redox homeostasis induced activation of calcium-independent phospholipase and alteration of glycerophospholipid metabolism.
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.
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Tzu-Ling
authors.initials: TL
authors.lastname: Chen
authors.affiliation: Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Yang
authors.affiliation: Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Hung
authors.affiliation: Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Meng-Hsin
authors.initials: MH
authors.lastname: Ou
authors.affiliation: Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yi-Yun
authors.initials: YY
authors.lastname: Pan
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.|Metabolomics Core Laboratory, Chang Gung University, Taoyuan, Taiwan.|Clinical Phenome Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.|Graduate Institute of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Cheng
authors.affiliation: New York University School of Medicine, New York,NY, USA.
authors.forename: Arnold
authors.initials: A
authors.lastname: Stern
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Szecheng J
authors.initials: SJ
authors.lastname: Lo
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.|Graduate Institute of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Pediatric Hematology/Oncology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Daniel Tsun-Yee
authors.initials: DT
authors.lastname: Chiu
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D021961:Cell Membrane Structures / Q000648:ultrastructure; D004528:Egg Shell / Q000648:ultrastructure; D047108:Embryonic Development / Q000235:genetics*; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics; D020404:Glycerophospholipids / Q000378:metabolism; D006706:Homeostasis; D010084:Oxidation-Reduction; D054512:Phospholipases A2, Calcium-Independent / Q000235:genetics*
chemical_list: D020404:Glycerophospholipids; D005954:Glucosephosphate Dehydrogenase; D054512:Phospholipases A2, Calcium-Independent