title: Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver.
abstract: Across phyla, reduced nicotinamide adenine dinucleotide phosphate (NADPH) transfers intracellular reducing power to thioredoxin reductase-1 (TrxR1) and glutathione reductase (GR), thereby supporting fundamental housekeeping and antioxidant pathways. Here we show that a third, NADPH-independent pathway can bypass the need for TrxR1 and GR in mammalian liver. Most mice genetically engineered to lack both TrxR1 and GR in all hepatocytes ('TR/GR-null livers') remain long-term viable. TR/GR-null livers cannot reduce oxidized glutathione disulfide using NADPH but still require continuous glutathione synthesis. Inhibition of cystathionine γ-lyase causes rapid necrosis of TR/GR-null livers, indicating that methionine-fueled trans-sulfuration supplies the necessary cysteine precursor for glutathione synthesis via an NADPH-independent pathway. We further show that dietary methionine provides the cytosolic disulfide-reducing power and all sulfur amino acids in TR/GR-null livers. Although NADPH is generally considered an essential reducing currency, these results indicate that hepatocytes can adequately sustain cytosolic redox homeostasis pathways using either NADPH or methionine.
authors: 1] Department of Microbiology and Immunology, Montana State University, Cooley Hall, PO Box 173520, Bozeman, Montana 59717, USA [2] Division of Biochemistry, Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors: Sofi
authors: S
authors: Eriksson
authors: Department of Microbiology and Immunology, Montana State University, Cooley Hall, PO Box 173520, Bozeman, Montana 59717, USA.
authors: Justin R
authors: JR
authors: Prigge
authors: Department of Microbiology and Immunology, Montana State University, Cooley Hall, PO Box 173520, Bozeman, Montana 59717, USA.
authors: Emily A
authors: EA
authors: Talago
authors: Division of Biochemistry, Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors: Elias S J
authors: ES
authors: Arnér
authors: Department of Microbiology and Immunology, Montana State University, Cooley Hall, PO Box 173520, Bozeman, Montana 59717, USA.
authors: Edward E
authors: EE
authors: Schmidt
mesh_terms: D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D005978:Glutathione / Q000096:biosynthesis*; D005980:Glutathione Reductase / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D010084:Oxidation-Reduction / Q000187:drug effects; D013462:Sulfur Radioisotopes; D054481:Thioredoxin Reductase 1 / Q000235:genetics
chemical_list: D013462:Sulfur Radioisotopes; D008715:Methionine; D005980:Glutathione Reductase; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D003542:Cystathionine gamma-Lyase; D005978:Glutathione; D003545:Cysteine