Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver

Nat Commun. 2015 Mar 20;6:6479. doi: 10.1038/ncomms7479.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystathionine gamma-Lyase / antagonists & inhibitors
  • Cystathionine gamma-Lyase / metabolism*
  • Cysteine / metabolism*
  • Cytosol / drug effects
  • Cytosol / metabolism*
  • Glutathione / biosynthesis*
  • Glutathione Reductase / genetics
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Homeostasis
  • Liver / drug effects
  • Liver / metabolism*
  • Methionine / metabolism*
  • Mice
  • Mice, Knockout
  • Necrosis
  • Oxidation-Reduction* / drug effects
  • Sulfur Radioisotopes
  • Thioredoxin Reductase 1 / genetics


  • Sulfur Radioisotopes
  • Methionine
  • Glutathione Reductase
  • Thioredoxin Reductase 1
  • Txnrd1 protein, mouse
  • Cystathionine gamma-Lyase
  • Glutathione
  • Cysteine