Glutathione prevents copper-induced cell death by binding cuprous ions independently of its reduced thiol group.

SAPORITO MAGRIÑÁ CRISTIAN; MUSACCO SEBIO ROSARIO; ANDRIEUX G; TUTTOLOMONDO, MV; DESIMONE MARTÍN; BÖRRIES MELANIE; BORNER C; REPETTO MARISA

Buenos Aires

Congreso; LXII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica.; 2017

Sociedad Argentina de Investigación Clínica.

Copper (Cu) accumulation is the underlying cause of toxicity inWilson disease and Cu imbalances have also been reportedly involvedin neurologic disorders such as Alzheimer and Parkinson diseases.The reaction between Cu1+ and H2O2 gives rise to hydroxylradical which is believed to drive the cytotoxic effects of intracellularCu accumulation. However, no antioxidant therapy could be so fardeveloped on this basis and the therapeutic strategies in Cu overloadedpatients rely fully on Cu chelating agents. Cu ions have beenreported to interact directly with proteins, altering their structure andfunction. Objective: To determine whether Cu-induced cell death isdriven by oxidative stress or impaired proteostasis. Methodology:heat shock response (HSR), unfolded protein response (UPR) andmitochondrial UPR (mtUPR), ubiquitin and autophagy related genesupon Cu overload in BEAS-2B cells were assessed with DNA microarrays.Potentiating effects on cell viability of pro-oxidizing (Fe)and pro-aggregating (Zn) stimuli on Cu loaded cells were assessedby flow cytometry. Protein aggregation was assessed by a turbidityassay. Results: A thorough HSR and a milder UPR with no mtUPRwas observed in cells exposed to Cu overload. Additionally, an inductionof ubiquitin, LC3 and GABARAPL1 was observed. Cu2+ wasable to directly induce protein aggregation in vitro in a time and concentrationdependent manner. Compared to other metals, Cu2+ wasthe most efficient in promoting protein aggregation followed by Zn.Interestingly, co-incubation of Cu loaded cells with Fe did not potentiatecell death while co-incubation with Zn drastically enhancedit. Cu exposure induced HSR and UPR due to impaired proteostasisin the cytosol and the endoplasmic reticulum respectively. Theability of Cu ions to directly interact with proteins seems to be theforce driving cell death as observed by the potentiating effect with Znwhich also promotes aggregation; while Fe, did not show any effect.