Regulation of the urea cycle by CPS1O-GlcNAcylation in response to dietary restriction and aging

Abstract

O-linked N-acetyl-glucosamine glycosylation (O-GlcNAcylation) of intracellular proteins is a dynamic process broadly implicated in age-related disease, yet it remains uncharacterized whether and how O-GlcNAcylation contributes to the natural aging process. O-GlcNAc transferase (OGT) and the opposing enzyme O-GlcNAcase (OGA) control this nutrient-sensing protein modification in cells. Here, we show that global O-GlcNAc levels are increased in multiple tissues of aged mice. In aged liver, carbamoyl phosphate synthetase 1 (CPS1) is among the most heavily O-GlcNAcylated proteins. CPS1 O-GlcNAcylation is reversed by calorie restriction and is sensitive to genetic and pharmacological manipulations of the O-GlcNAc pathway. High glucose stimulates CPS1 O-GlcNAcylation and inhibits CPS1 activity. Liver-specific deletion of OGT potentiates CPS1 activity and renders CPS1 irresponsive to further stimulation by a prolonged fasting. Our results identify CPS1 O-GlcNAcylation as a key nutrient-sensing regulatory step in the urea cycle during aging and dietary restriction, implying a role for mitochondrial O-GlcNAcylation in nutritional regulation of longevity.

Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin

“…We are also limited in that we did not examine off-target effects of overexpression of SIRT5 as a potential therapy. Furthermore, we noted that the enzymes of the urea cycle were intact, although the activities of each may be subjected to additional regulation that has yet to be explored via additional proteomic analyses and examination of epigenetic effects ( 72 ). The spectrum of effects mediated by PTMs is growing ( 73 ), and our studies firmly establish a critical role for SIRT5 in mediating the biochemical perturbations observed in MMA and, we believe, related disorders.…”

A sugary addition to the urea cycle

“…In a recent publication, Wu et al. (2022) asked a simple premise: how does aging impact O -GlcNAcylation in the liver?…”

“…Thus, changes in nutrient levels will impact OGT function and quickly lead to adaptive changes in most to all cellular processes. Returning to the work by Wu et al. (2022) , let us once again ask a simple question: how does aging impact O -GlcNAcylation?…”

“…Urea cycle deficiencies are linked to numerous diseases and contribute to higher ammonia levels in obese patients ( Nitzahn and Lipshutz, 2020 ). Intriguingly, Wu et al. (2022) link loss of urea cycle function to nutrient excess through O -GlcNAcylation.…”

“…Still, Wu et al. (2022) manage to generate some chewy but intriguing food for thought as we consider the old adage of ‘which came first, the chicken or the egg?’ Do disruptions in O -GlcNAc nutrient-sensing drive aging or does aging drive O -GlcNAc disruption?…”