Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control stress and healthspan in C. elegans

Abstract

Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders.

Metabolic Mechanism and Physiological Role of Glycerol 3-Phosphate in Pseudomonas aeruginosa PAO1

“…The cellular toxicity caused by the accumulation of G3P appears to be a phenomenon shared by both prokaryotes and eukaryotes, as the negative effects of excess G3P on growth have been observed in E. coli ( 9 , 48 ), S. cerevisiae ( 10 ), C. glutamicum ( 11 ), M. tuberculosis ( 49 ), and C. elegans ( 50 ). Moreover, HAD-like G3PPs that dephosphorylate G3P to glycerol and prevent an accumulation of G3P have been identified in S. cerevisiae ( 10 ), C. glutamicum ( 11 ), and C. elegans ( 50 ).…”

“…The cellular toxicity caused by the accumulation of G3P appears to be a phenomenon shared by both prokaryotes and eukaryotes, as the negative effects of excess G3P on growth have been observed in E. coli ( 9 , 48 ), S. cerevisiae ( 10 ), C. glutamicum ( 11 ), M. tuberculosis ( 49 ), and C. elegans ( 50 ). Moreover, HAD-like G3PPs that dephosphorylate G3P to glycerol and prevent an accumulation of G3P have been identified in S. cerevisiae ( 10 ), C. glutamicum ( 11 ), and C. elegans ( 50 ). In the present study, we identified and characterized the phosphatases PA0562 and PA3172 in P. aeruginosa PAO1, and the overexpression of PA0562 and PA3172 was found to alleviate G3P-induced growth inhibition, whereas the knockout of these two phosphatases potentiated the inhibitory effects of G3P ( Fig.…”

Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia

“…We earlier discovered a novel mammalian metabolic enzyme, lying at the heart of intermediary metabolism, Gro3P phosphatase (G3PP), and demonstrated that G3PP directly converts part of the excess glucose-derived Gro3P to less toxic glycerol, which leaves the cell [ 18 ]. We named this novel metabolic pathway the glycerol shunt that possibly helps in glucodetoxification in pancreatic β-cells [ 20 ] and demonstrated that G3PP-glycerol shunt pathway confers better healthspan and lifespan in C. elegans [ 21 ]. Hydrolytic control of intracellular Gro3P by G3PP adds another layer of metabolic regulation that was not recognized previously in mammalian cells.…”

Application of Caenorhabditis elegans in Lipid Metabolism Research

“…As the central metabolite at the crossroads of fat and the carbohydrate metabolism, Gro3P has been found in mammals to be directly converted to glycerol in the presence of glycerol-3-phosphate phosphatase (G3PP) (encoded by phosphoglycolate phosphatase , abbreviated as Pgp ) [ 62 ]. Surprisingly, three Pgp homologues have recently been identified in C. elegans as pgph and its protein products has possessed G3PP activity, which is essential for the synthesis of glycerol [ 63 ]. The overexpression of phosphoglycolate phosphatase homolog-2 ( pgph-2 ) enhanced the conversion of Gro3P to glycerol, thereby reducing adipogenesis in nematodes.…”