Copper-induced proteostatic stress: a redox independent damage pathway.

SAPORITO MAGRIÑÁ CRISTIAN; FACIO, MARIA LAURA; REPETTO, MARISA GABRIELA

Congreso; V International Congress in Translational Medicine.; 2021

Introduction: Copper (Cu) is a highly reactive metal involved in several physiological processes. Due to its reactivity, the concentration of this metal is tightly controlled within the cell as well as in the extracellular milieu. In the literature, the toxicity of Cu ions is usually linked to oxidative damage. However, no antioxidant therapy has ever been proven effective in treating any Cu-related pathology. In previous work, we have shown that while Cu may induce oxidative damage, the driving force of cell death is the direct interaction of the metal with proteins which alters their structure and disturbs proteostasis. We have also shown that Cu induces albumin aggregation at fairly high concentrations (higher than 300 uM). However, we speculated that albumin should also be highly resistant to Cu-induced aggregation due to its high plasmatic concentration. Results: In this work, we performed optic density kinetic analysis of isolated albumin, serum or plasma exposed to different concentrations of Cu. We observed that protein aggregation from healthy rat serum takes place at lower Cu concentrations (less than 100 uM) than albumin. No significant differences where observed between serum and plasma. The aggregation onset of serum proteins is dependent of Cu concentration but independent of protein concentration. Also, the aggregation curve of serum is flatter than that of albumin, likely due to the heterogeneous group of proteins present in serum. Indeed, the shape of the curve should be affected by the characteristic propensity to aggregation of each particular protein. Discussion: these results show that serum proteins can be aggregated by Cu ions at different concentrations. In terms of mass, the amount of protein aggregation at very low concentrations should be very low to induce pathological changes but this condition could change in adverse scenarios such as a prooxidant milieu, inflammation, fever, pH changes or any condition that would further impair protein homeostasis. Additionally, even in very low concentration, these protein aggregates might themselves mediate inflammatory processes that in the long term would be detrimental for the organism. Further research will be required to assess the involvement of Cu-mediated proteostatic stress in different pathologic processes.