Metabolomics of oxidative stress: Nrf2 independent depletion of NAD or increases of sugar alcohols

Chao Zhu, Haiwei Gu, Yan Jin, Daniel Wurm, Brian Freidhof, Yingying Lu, Qin M. Chen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Nrf2 encodes a transcription factor best known for regulating the expression of antioxidant and detoxification genes. Recent evidence suggested that Nrf2 mediates metabolic reprogramming in cancer cells. However, the role of Nrf2 in the biochemical metabolism of cardiac cells has not been studied. Using LC-MS/MS-based metabolomics, we addressed whether knocking out the Nrf2 gene in AC16 human cardiomyocytes affects metabolic reprogramming by oxidative stress. Profiling the basal level metabolites showed an elevated pentose phosphate pathway and increased levels of sugar alcohols, sorbitol, L-arabitol, xylitol and xylonic acid, in Nrf2 KO cells. With sublethal levels of oxidative stress, depletion of NAD, an increase of GDP and elevation of sugar alcohols, sorbitol and dulcitol, were detected in parent wild type (WT) cells. Knocking out Nrf2 did not affect these changes. Biochemical assays confirmed depletion of NAD in WT and Nrf2 KO cells due to H2O2 treatment. These data support that although Nrf2 deficiency caused baseline activation of the pentose phosphate pathway and sugar alcohol synthesis, a brief exposure to none-lethal doses of H2O2 caused NAD depletion in an Nrf2 independent manner. Loss of NAD may contribute to oxidative stress associated cell degeneration as observed with aging, diabetes and heart failure.

Original languageEnglish (US)
Article number115949
JournalToxicology and Applied Pharmacology
Volume442
DOIs
StatePublished - May 1 2022

Keywords

  • Cardiomyocytes
  • NAD
  • Nrf2 knockout
  • Pentose phosphate pathway
  • Sugar alcohols

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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