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

Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver.

Author information

1
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.
2
Department of Microbiology and Immunology, Montana State University, Cooley Hall, PO Box 173520, Bozeman, Montana 59717, USA.
3
Division of Biochemistry, Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

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.

PMID:
25790857
PMCID:
PMC4369796
DOI:
10.1038/ncomms7479
[Indexed for MEDLINE]
Free PMC Article

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