Universität zu Köln

Umansky, Carla ORCID: 0000-0002-9364-3544, Morellato, Agustin E., Rieckher, Matthias ORCID: 0000-0002-1945-9474, Scheidegger, Marco A., Martinefski, Manuela R., Fernandez, Gabriela A., Pak, Oleg, Kolesnikova, Ksenia, Reingruber, Hernan, Bollini, Mariela, Crossan, Gerry P., Sommer, Natascha ORCID: 0000-0002-8915-7762, Monge, Maria Eugenia, Schumacher, Bjorn and Pontel, Lucas B. (2022). Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity. Nat. Commun., 13 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

Formaldehyde (FA) is known to exert cytotoxicity through DNA damage. Here, the authors show that FA also triggers cellular redox imbalance by reacting with glutathione (GSH), and that FA cytotoxicity is prevented by GSH synthesis and by ADH5, an enzyme that metabolizes FA-GSH products. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Umansky, Carla UNSPECIFIED orcid.org/0000-0002-9364-3544 UNSPECIFIED Morellato, Agustin E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rieckher, Matthias UNSPECIFIED orcid.org/0000-0002-1945-9474 UNSPECIFIED Scheidegger, Marco A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Martinefski, Manuela R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fernandez, Gabriela A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pak, Oleg UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolesnikova, Ksenia UNSPECIFIED UNSPECIFIED UNSPECIFIED Reingruber, Hernan UNSPECIFIED UNSPECIFIED UNSPECIFIED Bollini, Mariela UNSPECIFIED UNSPECIFIED UNSPECIFIED Crossan, Gerry P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sommer, Natascha UNSPECIFIED orcid.org/0000-0002-8915-7762 UNSPECIFIED Monge, Maria Eugenia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumacher, Bjorn UNSPECIFIED UNSPECIFIED UNSPECIFIED Pontel, Lucas B. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-685624
DOI:	10.1038/s41467-022-28242-7
Journal or Publication Title:	Nat. Commun.
Volume:	13
Number:	1
Date:	2022
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FANCONI-ANEMIA; DNA-DAMAGE; DEFECTIVE HEMATOPOIESIS; S-NITROSOGLUTATHIONE; DEFICIENCY; METABOLISM; MECHANISM; PATHWAYS; REPAIR; ALCOHOL Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68562