Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver

Sofi Eriksson, Justin R. Prigge, Emily A. Talago, Elias S.J. Arnér and Edward E. Schmidt ()
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Sofi Eriksson: Montana State University
Justin R. Prigge: Montana State University
Emily A. Talago: Montana State University
Elias S.J. Arnér: Medical Biochemistry and Biophysics, Karolinska Institutet
Edward E. Schmidt: Montana State University

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7479

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