Nucleotide metabolism is linked to cysteine availability

Journal of Biological ChemistryJournal of Biological ChemistryVolume 299, Issue 4, April 2023, 103039Journal home page for Journal of Biological ChemistryAuthor links open overlay panel, , , ,

The small molecule erastin inhibits the cystine-glutamate antiporter, system xc-, which leads to intracellular cysteine and glutathione depletion. This can cause ferroptosis, which is an oxidative cell death process characterized by uncontrolled lipid peroxidation. Erastin and other ferroptosis inducers have been shown to affect metabolism but the metabolic effects of these drugs have not been systematically studied. To this end, we investigated how erastin impacts global metabolism in cultured cells and compared this metabolic profile to that caused by the ferroptosis inducer RAS-selective lethal 3 or in vivo cysteine deprivation. Common among the metabolic profiles were alterations in nucleotide and central carbon metabolism. Supplementing nucleosides to cysteine-deprived cells rescued cell proliferation in certain contexts, showing that these alterations to nucleotide metabolism can affect cellular fitness. While inhibition of the glutathione peroxidase GPX4 caused a similar metabolic profile as cysteine deprivation, nucleoside treatment did not rescue cell viability or proliferation under RAS-selective lethal 3 treatment, suggesting that these metabolic changes have varying importance in different scenarios of ferroptosis. Together, our study shows how global metabolism is affected during ferroptosis and points to nucleotide metabolism as an important target of cysteine deprivation.

Keywords

Cysteine

nucleotide

ferroptosis

erastin

glutathione

metabolism

AbbreviationsPDH

pyruvate dehydrogenase

RNR

ribonucleotide reductase

© 2023 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.

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