Endogenous formaldehyde scavenges cellular glutathione resulting in cytotoxic redox disruption

Carla Umansky, Agustín Morellato, Marco Scheidegger, Matthias Rieckher, Manuela R. Martinefski, Gabriela A. Fernandez, Ksenia Kolesnikova, Anna J. Vesting, Ismene Karakasilioti, Hernán Reingruber, Yan Wei, Rongqiao He, Mariela Bollini, María Eugenia Monge, Björn Schumacher and Lucas B. Pontel

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Received Date: 24th April 20

Formaldehyde (FA) is a ubiquitous endogenous and environmental metabolite that is thought to exert cytotoxicity through DNA and DNA-protein crosslinking. We show here that FA can cause cellular damage beyond genotoxicity by triggering oxidative stress, which is prevented by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR). Mechanistically, we determine that endogenous FA reacts with the redox-active thiol group of glutathione (GSH) forming S-hydroxymethyl-GSH, which is metabolized by ADH5 yielding reduced GSH thus preventing redox disruption. We identify the ADH5-ortholog gene in Caenorhabditis elegans and show that oxidative stress also underlies FA toxicity in nematodes. Moreover, we show that endogenous GSH can protect cells lacking the Fanconi Anemia DNA repair pathway from FA, which might have broad implications for Fanconi Anemia patients and for healthy BRCA2-mutation carriers. We thus establish a highly conserved mechanism through which endogenous FA disrupts the GSH-regulated cellular redox homeostasis that is critical during development and aging.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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