IDH-1 deficiency induces growth defects and metabolic alterations in GSPD-1-deficient Caenorhabditis elegans

Hung Chi Yang, Hsiang Yu, You Cheng Liu, Tzu Ling Chen, Arnold Stern, Szecheng J. Lo, Daniel Tsun Yee Chiu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

17 Scopus citations

Abstract

NADPH is a reducing equivalent that maintains redox homeostasis and supports reductive biosynthesis. Lack of major NADPH-producing enzymes predisposes cells to growth retardation and demise. It was hypothesized that double deficiency of the NADPH-generating enzymes, GSPD-1 (Glucose-6-phosphate 1-dehydrogenase), a functional homolog of human glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, and IDH-1 (isocitrate dehydrogenase-1) affect growth and development in the nematode, Caenorhabditis elegans (C. elegans). The idh-1;gspd-1(RNAi) double-deficient C. elegans model displayed shrinkage of body size, growth retardation, slowed locomotion, and impaired molting. Global metabolomic analysis was employed to address whether or not metabolic pathways were altered by severe NADPH insufficiency by the idh-1;gspd-1(RNAi) double-deficiency. The principal component analysis (PCA) points to a distinct metabolomic profile of idh-1;gspd-1(RNAi) double-deficiency. Further metabolomic analysis revealed that NADPH-dependent and glutamate-dependent amino acid biosynthesis were significantly affected. The reduced pool of amino acids may affect protein synthesis, as indicated by the absence of NAS-37 expression during the molting process. In short, double deficiency of GSPD-1 and IDH-1 causes growth retardation and molting defects, which are, in part, attributed to defective protein synthesis, possibly mediated by altered amino acid biosynthesis and metabolism in C. elegans.

Original languageEnglish
Pages (from-to)385-396
Number of pages12
JournalJournal of Molecular Medicine
Volume97
Issue number3
DOIs
StatePublished - 07 03 2019

Bibliographical note

Publisher Copyright:
© 2018, The Author(s).

Keywords

  • Amino acid
  • C. elegans
  • Development
  • GSPD-1
  • IDH-1
  • Metabolomic
  • Molting

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