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Resources » Paper

Umansky C et al. (2022) Nat Commun "Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity."

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  • Comments on Umansky C et al. (2022) Nat Commun "Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity." (0)

  • Overview

    PMID:
    35136057
    DOI:
    10.1038/s41467-022-28242-7
    Status:
    Publication type:
    Journal_article
    WormBase ID:
    WBPaper00062505

    Umansky C, Morellato AE, Rieckher M, Scheidegger MA, Martinefski MR, Fernandez GA, Pak O, Kolesnikova K, Reingruber H, Bollini M, Crossan GP, Sommer N, Monge ME, Schumacher B, & Pontel LB (2022). Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity. Nat Commun, 13, 745. doi:10.1038/s41467-022-28242-7

    Formaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking, likely contributing to the onset of the human DNA repair condition Fanconi Anaemia. Mutations in the genes coding for FA detoxifying enzymes underlie a human inherited bone marrow failure syndrome (IBMFS), even in thepresence of functional DNA repair, raising the question of whether FA causes relevant cellular damage beyond genotoxicity. Here, we report that FA triggers cellular redox imbalance in human cells and in Caenorhabditis elegans. Mechanistically, FA reacts with the redox-active thiol group of glutathione (GSH), altering the GSH:GSSG ratio and causing oxidative stress. FA cytotoxicity is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), which metabolizes FA-GSH products, lastly yielding reduced GSH. Furthermore, we show that GSH synthesis protects human cells from FA, indicating an active role of GSH in preventing FA toxicity. These findings might be relevant for patients carrying mutations in FA-detoxification systems and could suggest therapeutic benefits from thiol-rich antioxidants like N-acetyl-L-cysteine.

    Authors: Umansky C, Morellato AE, Rieckher M, Scheidegger MA, Martinefski MR, Fernandez GA, Pak O, Kolesnikova K, Reingruber H, Bollini M, Crossan GP, Sommer N, Monge ME, Schumacher B, Pontel LB


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