Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity

Carla Umansky, Agustín E. Morellato, Matthias Rieckher, Marco A. Scheidegger, Manuela R. Martinefski, Gabriela A. Fernández, Oleg Pak, Ksenia Kolesnikova, Hernán Reingruber, Mariela Bollini, Gerry P. Crossan, Natascha Sommer, María Eugenia Monge, Björn Schumacher and Lucas B. Pontel ()
Additional contact information
Carla Umansky: CONICET - Partner Institute of the Max Planck Society
Agustín E. Morellato: CONICET - Partner Institute of the Max Planck Society
Matthias Rieckher: University of Cologne, and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), and Center for Molecular Medicine Cologne (CMMC)
Marco A. Scheidegger: CONICET - Partner Institute of the Max Planck Society
Manuela R. Martinefski: Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Gabriela A. Fernández: Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Oleg Pak: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL)
Ksenia Kolesnikova: University of Cologne, and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), and Center for Molecular Medicine Cologne (CMMC)
Hernán Reingruber: CONICET - Partner Institute of the Max Planck Society
Mariela Bollini: Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Gerry P. Crossan: Cambridge Biomedical Campus, Francis Crick Avenue
Natascha Sommer: Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL)
María Eugenia Monge: Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Björn Schumacher: University of Cologne, and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), and Center for Molecular Medicine Cologne (CMMC)
Lucas B. Pontel: CONICET - Partner Institute of the Max Planck Society

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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 the presence 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.

Date: 2022
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DOI: 10.1038/s41467-022-28242-7

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