Integration of carbohydrate metabolism and redox state controls dauer larva formation in Caenorhabditis elegans.
Under adverse conditions, Caenorhabditis elegans enters a diapause stage called the dauer larva. External cues signal the nuclear hormone receptor DAF-12, the activity of which is regulated by its ligands: dafachronic acids (DAs). DAs are synthesized from cholesterol, with the last synthesis step requiring NADPH, and their absence stimulates dauer formation. Here we show that NADPH levels determine dauer formation in a regulatory mechanism involving key carbohydrate and redox metabolic enzymes. Elevated trehalose biosynthesis diverts glucose-6-phosphate from the pentose phosphate pathway, which is the major source of cellular NADPH. This enhances dauer formation due to the decrease in the DA level. Moreover, DAF-12, in cooperation with DAF-16/FoxO, induces negative feedback of DA synthesis via activation of the trehalose-producing enzymes TPS-1/2 and inhibition of the NADPH-producing enzyme IDH-1. Thus, the dauer developmental decision is controlled by integration of the metabolic flux of carbohydrates and cellular redox potential.
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany.
Sider
S
Penkov
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany.
Damla
D
Kaptan
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany.
Cihan
http://orcid.org/0000-0003-4378-9075
C
Erkut
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany.
Mihail
M
Sarov
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany.
Fanny
F
Mende
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden 01307, Germany.
Teymuras V
TV
Kurzchalia
D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D050260:Carbohydrate Metabolism; D018507:Gene Expression Regulation, Developmental; D007814:Larva / Q000502:physiology; D009154:Mutation; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D034622:RNA Interference; D014199:Trehalose / Q000096:biosynthesis
D029742:Caenorhabditis elegans Proteins; D009249:NADP; D014199:Trehalose