The multifaceted roles of glutathione in the cellular protection against toxic metabolites

LUCAS PONTEL

Trieste

Exposición; Scientific seminar at Reproduction and Developmental Sciences of University of Trieste; 2023

Universidad de Trieste

The continuous exposure of cells to electrophilic metabolites such as aldehydes and reactive oxygen species can cause cellular damage by reacting with electron-rich groups present in nucleic acids and proteins, leading to cell poisoning and potentially driving tumorigenesis and human diseases such as Fanconi Anemia. However, cells possess detoxifying enzymes and can increase levels of cellular antioxidants, such as glutathione (GSH), to mitigate the toxicity of these harmful molecules.Recently, we reported that GSH plays a critical role in limiting the toxicity of the environmental mutagen formaldehyde (FA) by initiating its metabolism. However, if FA metabolism fails, the reaction between FA and GSH can alter the cellular redox balance, leading to oxidative stress and contributing to FA toxicity. In addition, we have identified that blocking GSH synthesis is a potential therapeutic intervention for acute lymphoblastic leukaemia (ALL) cells. Our data indicate that the underlying cause of this dependency is the epigenetic silencing of FSP1, a GSH-independent factor that counters a type of cell death known as ferroptosis. Thus, blocking the GSH-dependent pathway leaves ALL cells vulnerable to FA toxicity and to ferroptosis inducers. In sum, these findings shed light on possible applications of ferroptosis inducers in ALL treatment and provide new insights into the toxicity mechanisms of mutagens such as FA.