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Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity.
Umansky, Carla; Morellato, Agustín E; Rieckher, Matthias; Scheidegger, Marco A; Martinefski, Manuela R; Fernández, Gabriela A; Pak, Oleg; Kolesnikova, Ksenia; Reingruber, Hernán; Bollini, Mariela; Crossan, Gerry P; Sommer, Natascha; Monge, María Eugenia; Schumacher, Björn; Pontel, Lucas B.
Afiliación
  • Umansky C; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET - Partner Institute of the Max Planck Society, C1425FQD, Buenos Aires, Argentina.
  • Morellato AE; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET - Partner Institute of the Max Planck Society, C1425FQD, Buenos Aires, Argentina.
  • Rieckher M; Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), and Center for Molecular Medicine Cologne (CMMC), 50931, Cologne, Germany.
  • Scheidegger MA; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET - Partner Institute of the Max Planck Society, C1425FQD, Buenos Aires, Argentina.
  • Martinefski MR; Centro de Investigaciones en Bionanociencias (CIBION), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1425FQD, Buenos Aires, Argentina.
  • Fernández GA; Centro de Investigaciones en Bionanociencias (CIBION), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1425FQD, Buenos Aires, Argentina.
  • Pak O; Justus-Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
  • Kolesnikova K; Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), and Center for Molecular Medicine Cologne (CMMC), 50931, Cologne, Germany.
  • Reingruber H; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET - Partner Institute of the Max Planck Society, C1425FQD, Buenos Aires, Argentina.
  • Bollini M; Centro de Investigaciones en Bionanociencias (CIBION), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1425FQD, Buenos Aires, Argentina.
  • Crossan GP; MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
  • Sommer N; Justus-Liebig University, Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
  • Monge ME; Centro de Investigaciones en Bionanociencias (CIBION), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), C1425FQD, Buenos Aires, Argentina.
  • Schumacher B; Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, and Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), and Center for Molecular Medicine Cologne (CMMC), 50931, Cologne, Germany.
  • Pontel LB; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET - Partner Institute of the Max Planck Society, C1425FQD, Buenos Aires, Argentina. lpontel@ibioba-mpsp-conicet.gov.ar.
Nat Commun ; 13(1): 745, 2022 02 08.
Article en En | MEDLINE | ID: mdl-35136057
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Caenorhabditis elegans / Aldehído Oxidorreductasas / Anemia de Fanconi / Formaldehído / Glutatión Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Argentina Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Caenorhabditis elegans / Aldehído Oxidorreductasas / Anemia de Fanconi / Formaldehído / Glutatión Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Argentina Pais de publicación: Reino Unido