Copper, Cuproptosis, and Neurodegenerative Diseases

Abstract

Copper is a vital micronutrient for animals and plants acting as a crucial cofactor in the synthesis of numerous metabolic enzymes and contributing to mitochondrial respiration, metabolism, oxido-reductive reactions, signal transmission, and oxidative and nitrosative damage. In the cells, copper may exist in the Cu⁺ and Cu⁺⁺ oxidation states and the interconversion between these two states may occur via various redox reactions regulating cellular respiration, energy metabolism, and cell growth. The human body maintains a low level of copper, and copper deficiency or copper excess may adversely affect cellular functions; therefore, regulation of copper levels within a narrow range is important for maintaining metabolic homeostasis. Recent studies identified a new copper-dependent form of cell death called cuproptosis. Cuproptosis occurs due to copper binding to lipoylated enzymes (for instance, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the tricarboxylic acid Krebs cycle. In recent years, extensive studies on copper homeostasis and copper-induced cell death in degenerative disorders, like Menkes, Wilson, Alzheimer, Parkinson's, Huntington's diseases, and Amyotrophic Lateral Sclerosis, have discussed the therapeutic potential of targeting cuproptosis. Copper contamination in the environment, which has increased in recent years due to the expansion of agricultural and industrial activities, is associated with a wide range of human health risks. Soil used for the cultivation of grapes has a long history of copper-based fungicide application (the Bordeaux mixture is rich in copper) resulting in copper accumulation at levels capable of causing toxicity in plants that co-inhabit the vineyards. Phytoremediation, which uses plants and biological solutions to remove toxic heavy metals and pesticides and other contaminants from soil and water, is an environmentally friendly and cost-effective technology used for the removal of copper. It requires plants to be tolerant of high levels of copper and capable of accumulating metal copper in plants' aerial organs and roots. This review aims at highlighting the importance of copper as an essential metal, as well as its involvement in cuproptosis and neurodegenerative diseases.

Keywords: chelating drugs; copper; copper homeostasis; cuproptosis; mitochondria; neurodegenerative diseases.

Figure 1

Copper metabolism and trafficking in mammalian cells. The uptake of Cu⁺ via SLC31A1/CTR1 depends on the Cu⁺⁺ reduction to Cu⁺ by six-transmembrane epithelial antigen of prostate (STEAP) family of metalloreductase. In the cytosol of enterocytes, Cu⁺ is bound to a non-proteinaceous ligand, like GSH or L (Cu⁺GSH or Cu⁺L) and then is transferred to SOD1 (Cu⁺SOD1). Copper is delivered to the Golgi lumen thanks to antioxidant ATOX1 and the Golgi Cu pumps ATP7A/B, located in the trans-Golgi network (TGN). Excess copper is pumped out of the cell thanks to ATP7A/B. Copper is also transported to the mitochondrial matrix by the Cu transport protein 3 (SLC25A3). The nuclear histones H3-H4 act as a copper reductase.

Figure 2

Copper trafficking in mitochondria. Copper bound to a ligand (Cu⁺L) enters mitochondria via outer membrane porin and then SLC25A3 transports it into the matrix. In the matrix copper binds cytochrome C oxidase copper chaperone 17 (COX17) that is a Cu donor to SCO1, SCO2, and COX11 to mediate copper insertion into COX. Excess Cu in mitochondrial matrix, via Fenton-like reaction, induces ROS, lipid peroxidation, and DNA damage.

Figure 3

Cuproptosis mechanism. Copper ionophores (elesclomol and diethyldithiocarbamate) capture Cu⁺⁺ to transport it into mitochondria. FDX1 reduces Cu⁺⁺ to Cu⁺ and allows the lipoylation of mitochondrial proteins in the presence of lipoic acid synthase (LIAS). Cu⁺ induces the aggregation of lipoylated proteins and at the same time depletes Fe-S clusters by inducing cuproptosis. The lipoylation is a highly conserved post-translational reaction affecting specific lysine residues in four complexes of Krebs cycle. Among them, dihydrolipoamide S-acetyltransferase (DLAT) and dihydrolipoamide S-succinyltransferase (DLST) are components of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, which catalyze the conversion of pyruvate to acetyl CoA and α-ketoglutarate to succinyl CoA, respectively. This process of cell death can by mitigated in the presence of copper-chelating agents like tetrathiomolibdate (TTM) or dimercapto succinic acid (DMSA).