Deadly excess copper

Abstract

Higher eukaryotes' life is impossible without copper redox activity and, literally, every breath we take biochemically demonstrates this. However, this dependence comes at a considerable price to ensure target-oriented copper action. Thereto its uptake, distribution but also excretion are executed by specialized proteins with high affinity for the transition metal. Consequently, malfunction of copper enzymes/transporters, as is the case in hereditary Wilson disease that affects the intracellular copper transporter ATP7B, comes with serious cellular damage. One hallmark of this disease is the progressive copper accumulation, primarily in liver but also brain that becomes deadly if left untreated. Such excess copper toxicity may also result from accidental ingestion or attempted suicide. Recent research has shed new light into the cell-toxic mechanisms and primarily affected intracellular targets and processes of such excess copper that may even be exploited with respect to cancer therapy. Moreover, new therapies are currently under development to fight against deadly toxic copper.

Keywords: Acute copper toxicity; Mitochondria; Wilson disease.

Fig. 1

Copper is taken up into hepatocytes via DMT1 or after reduction by the STEAP proteins by CTR1. Cuprous copper is then bound by ATOX1, which delivers copper to the TGN. Here, ATP7B mediates either incorporation into ceruloplasmin for further distribution in the body via circulation or excretion via the bile. Copper transport to the mitochondria occurs via an unidentified copper ligand (CuL), which delivers copper to the uptake transporter SLC25A3. Thereupon, with help of several copper chaperons, it gets either incorporated into the CuA/B sites of the cytochrome c-oxidase (COX1) or into the superoxide dismutase 1 (SOD1). Created with BioRender.com.

Fig. 2

Mechanism of Cu-catalyzed ROS production. In presence of dioxygen and a reducing agent (Red) copper may catalyze the activation of oxygen by cycling between its cuprous and cupric redox state. Possible reducing agents are ascorbate (AscH), glutathione (GSH) and cysteine (Cys). Figure taken from “Revisiting the pro-oxidant activity of copper: interplay of ascorbate, cysteine, and glutathione” by Falcone, E. et al. Metallomics. 2023 Jul 10; 15(7): mfad040. https://doi.org/10.1093/mtomcs/mfad040 with permission (open access, distributed under the terms of the Creative Commons CC BY). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Copper induced mitochondrial structure alterations in WD rat livers. A Electron micrographs of liver in situ. Diseased WD rats have altered liver mitochondria with electron translucent widened cristae (arrows) and detached outer membranes (arrowheads). B Electron micrographs of isolated rat liver mitochondria from the same animals. Mitochondria from the diseased animal are structurally altered compared to mitochondria from heterozygous control animals. Membrane detachments, membranous inclusions and dilated cristae are apparent. Pictures adapted from Einer, C. et al. Gastroenterology. 2023 Jul; 165(1):187–200.e7. https://doi.org/10.1053/j.gastro.2023.03.216 with permission.

Fig. 4

Representative copper chelators currently in the clinics or in development for clinical use. Structures were illustrated by using ChemDraw Professional, Revity Signals Software. Sources: BAL [214], d-penicillamine [220], trientine [231], Chel2 [256], DPA-based chelator [258], DMP-1001 [259], methanobactins Ob3B and SB2 [264].