Copper homeostasis and cuproptosis in central nervous system diseases

Abstract

Copper (Cu), an indispensable micronutrient for the sustenance of living organisms, contributes significantly to a vast array of fundamental metabolic processes. The human body maintains a relatively low concentration of copper, which is mostly found in the bones, liver, and brain. Despite its low concentration, Cu plays a crucial role as an indispensable element in the progression and pathogenesis of central nervous system (CNS) diseases. Extensive studies have been conducted in recent years on copper homeostasis and copper-induced cell death in CNS disorders, including glioma, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease, and stroke. Cuproptosis, a novel copper-induced cell death pathway distinct from apoptosis, necrosis, pyroptosis, and ferroptosis, has been identified as potentially intricately linked to the pathogenic mechanisms underlying various CNS diseases. Therefore, a systematic review of copper homeostasis and cuproptosis and their relationship with CNS disorders could deepen our understanding of the pathogenesis of these diseases. In addition, it may provide new insights and strategies for the treatment of CNS disorders.

Fig. 1. Timeline of the history and milestones of cell death modalities.

The review summarizes the time of the discovery of 12 methods of cell death, including cuproptosis, and associated important figures.

Fig. 2. Mammalian copper metabolism at the molecular level.

Cu²⁺ is reduced to Cu⁺ with the participation of STEAP, and CTR1 is highly specific for Cu⁺ uptake. Copper-transporting ATPases are located in the TGN, where they pump Cu⁺ from the cytoplasm into the TGN lumen. These copper-transporting ATPases fuse with the plasma membrane to export Cu⁺ when intracellular Cu⁺ increases. Cu⁺ can be sequestered by MT1/2 for storage. Copper is transported by ATP7A through the basolateral membrane of enterocytes into the portal circulation, where it reaches the liver, the primary organ for storing copper. Via ATP7B, extra copper in liver cells is released as vesicles into bile. Cu⁺ is transported by CP to the whole-body system. In addition, Cu⁺ is carried to the nucleus through ATOX1, where it binds to transcription factors to promote the expression of certain genes. To trigger the function of the respiratory chain’s enzymes, COX17 carries Cu⁺ to the SCO1, SCO2, and COX11 which carry copper, and then delivers it to CCO. Cu⁺ can be transferred from CCS to SOD1.

Fig. 3. Schematic of cuproptosis mechanism.

Extracellular Cu is bound by Cu ionophores like elesclomol and moved into intracellular compartments. Cu then attaches itself to lipoylated mitochondrial TCA cycle enzymes, like DLAT, causing these proteins to aggregate. As the upstream regulator of protein lipoylation, FDX1/LIAS promotes the loss of Fe-S clusters and the aggregation of mitochondrial proteins. These aberrant processes ultimately result in cell demise via proteotoxic stress. Copper chelators such as GSH inhibit cuproptosis.

Fig. 4

Several common modes of cell death and their major mechanisms.

Fig. 5. Therapeutic focus of different diseases.

Copper overload promotes the progression of neurodegenerative diseases, with excess copper accumulating in diseased areas, leading to nerve cell death, neuroinflammation, and the development of oxidative stress. The therapeutic strategy focuses on the removal of copper accumulation at the lesion site by copper chelators to reduce neurotoxicity. However, it is not quite the same with tumors. On the one hand, copper promotes the proliferation and metastasis of tumor cells. The progression of tumor cells can be inhibited by copper chelators. On the other hand, large amounts of copper can induce cuproptosis in tumor cells. Tumor growth can be inhibited by copper ionophores and Cu-based nanomaterials.