Serine and glycine physiology reversibly modulate retinal and peripheral nerve function

Lim, EW; Fallon, RJ; Bates, C; Ideguchi, Y; Nagasaki, T; Handzlik, MK; Joulia, E; Bonelli, R; Green, CR; Ansell, BRE; Kitano, M; Polis, I; Roberts, AJ; Shigeki, F; Allikmets, R; Wallace, M; Friedlander, M; Metallo, CM; Gantner, ML

Author(s): Lim, EW; Fallon, RJ; Bates, C; Ideguchi, Y; Nagasaki, T; Handzlik, MK; Joulia, E; Bonelli, R; Green, CR; Ansell, BRE; Kitano, M; Polis, I; Roberts, AJ; Shigeki, F; Allikmets, R; Wallace, M; Friedlander, M; Metallo, CM; Gantner, ML;
Details: Publication Year 2024-08-26,Volume 36,Issue #10,Page 2315-2328 e6
Journal Title: Cell Metabolism
Abstract: Metabolic homeostasis is maintained by redundant pathways to ensure adequate nutrient supply during fasting and other stresses. These pathways are regulated locally in tissues and systemically via the liver, kidney, and circulation. Here, we characterize how serine, glycine, and one-carbon (SGOC) metabolism fluxes across the eye, liver, and kidney sustain retinal amino acid levels and function. Individuals with macular telangiectasia (MacTel), an age-related retinal disease with reduced circulating serine and glycine, carrying deleterious alleles in SGOC metabolic enzymes exhibit an exaggerated reduction in circulating serine. A Phgdh(+/)(-) mouse model of this haploinsufficiency experiences accelerated retinal defects upon dietary serine/glycine restriction, highlighting how otherwise silent haploinsufficiencies can impact retinal health. We demonstrate that serine-associated retinopathy and peripheral neuropathy are reversible, as both are restored in mice upon serine supplementation. These data provide molecular insights into the genetic and metabolic drivers of neuro-retinal dysfunction while highlighting therapeutic opportunities to ameliorate this pathogenesis.
Publisher: Elsevier
Keywords: MacTel; Phgdh; glycine; glycine cleavage; one-carbon metabolism; retina metabolism; serine; serine supplementation; sphingolipids; stable-isotope tracing
Research Division(s): Population Health And Immunity
PubMed ID: 39191258
Publisher's Version: https://doi.org/10.1016/j.cmet.2024.07.021
Open Access at Publisher's Site: https://doi.org/10.1016/j.cmet.2024.07.021
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-09-02 10:42:07

Last Modified: 2024-10-09 01:24:38