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Nat Commun ; 13(1): 745, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35136057

RESUMO

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.


Assuntos
Aldeído Oxirredutases/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Anemia de Fanconi/metabolismo , Formaldeído/toxicidade , Glutationa/metabolismo , Aldeído Oxirredutases/genética , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Dano ao DNA , Modelos Animais de Doenças , Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Formaldeído/metabolismo , Técnicas de Inativação de Genes , Células HCT116 , Humanos , Oxirredução , Estresse Oxidativo
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