Endogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity

Carla Umansky,Oleg Pak,Manuela R Martinefski,Hernán Reingruber,Ksenia Kolesnikova,Marco A Scheidegger,Björn Schumacher,Lucas B Pontel,Gerry P Crossan,Natascha Sommer,Gabriela A Fernández,Matthias Rieckher,María Eugenia Monge,Mariela Bollini,Agustín E Morellato

doi:10.1038/s41467-022-28242-7

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.

Highlights

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
Despite that ΔADH5 and ΔFANCB cells were significantly sensitive to physiological levels of FA, γ-H2AX was detected in the presence of FA in ΔFANCB but not in ΔADH5 cells (Fig. 1b, c), indicating that FA impairs cell viability when DNA repair is intact, but without triggering the DNA damage marker γ-H2AX
These observations are in agreement with previous findings reporting that γ-H2AX was induced by FA in ΔFANCD2 but not in wild type (WT) or ΔADH5 chicken DT40 cells[11]

Summary

Introduction

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. Human Fanconi Anaemia patients carrying a mutation in the gene coding for the acetaldehyde/FA catabolizing enzyme aldehyde dehydrogenase 2 (ALDH2) present accelerated progression of bone marrow failure (BMF)[13]. In the absence of mutations in DNA repair-coding genes, FA can underly a variant of a human inherited bone marrow failure syndrome (IBMFS) caused by mutations in both ALDH2 and ADH510, 14. This syndrome has been termed IBMFS/AMeD (Aplastic anaemia, Mental retardation, and Dwarfism) and it is manifested by early myelodysplasia, mental and growth retardation, and dwarfism[10, 14]. The simultaneous inactivation of Adh[5] and Aldh[2] in mice results in FA-

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Conclusion