Abstract
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.
Highlights
Under adverse conditions, Caenorhabditis elegans enters a diapause stage called the dauer larva
Trehalose-6-phosphate is synthesized by trehalose-6-phosphate synthase (TPS), which is encoded by the genes tps-1 and tps-2
This study investigated how carbohydrate metabolism and NADPH availability affect dauer formation
Summary
Caenorhabditis elegans enters a diapause stage called the dauer larva. 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. We showed that methylation of cholesterol in the fourth position by the sterol methylase STRM-1 renders cholesterol unsuitable for DA synthesis[15] Another cofactor for DA production is cytosolic NADPH, which is used by DAF-9 as an electron donor[13]. We show that the level of cytosolic NADPH determines dauer formation and is regulated by the biosynthesis of the disaccharide trehalose, which diverts glucose-6-phosphate (G6P) from the pentose phosphate pathway (PPP), the major source of NADPH in the cell. The developmental switch (reproductive to dauer) is directly connected to the metabolic flux of carbohydrates as well as to cellular redox potential
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