copper is an essential factor in all organisms, and once copper concentrations exceed the threshold maintained by homeostatic mechanisms, then copper in the body becomes toxic
the balance of copper as an important cofactor is crucial, as dysregulation of intracellular copper bioavailability will induce cytotoxicity and oxidative stress
in both prokaryotes and eukaryotes, copper homeostasis is finely regulated with the main aim of preventing excessive accumulation of copper ions in the cell and thus threatening cell survival
copper delivery is accomplished by the concerted action of a set of evolutionarily conserved transporters and metallochaperones
Copper homeostasis
copper homeostasis in mammals requires complex regulation of absorption and excretion
copper is taken up across the lumen surface of the small intestinal microvilli as cuprous ion by Ctr1
within the cell, copper is escorted to specific compartments by metallo-chaperones 1)
CCS, donates copper to superoxide dismutase
COX17, delivers copper to additional chaperones within the mitochondria for synthesis of cytochrome c oxidase
Atox1, delivers copper to the secretory pathway by docking with 2 P-type ATPases
ATP7A, is the protein nonfunctional in Menkes disease
ATP7A is required for cuproenzyme biosynthesis, and in the enterocyte it is required for copper efflux to portal blood
ATP7B, predominantly expressed in liver, is required for copper metallation of ceruloplasmin and biliary copper excretion
intracellular hepatic copper-binding proteins COMMD1 (copper metabolism MURR1 domain) and XIAP (X-linked inhibitor of apoptosis protein) may also be required for copper excretion
other proteins involved in copper homeostasis may include metallothionein and amyloid precursor protein
copper transportation in plasma from the intestine to liver and in systemic circulation probably includes binding to both albumin and α2-macroglobulin
Physiologic mechanisms
cuprotosis - copper induced cell death
in human cells, copper-dependent death occurs through direct binding of copper to lipid acylated components, which leads to aggregation of lipid acylated proteins and loss of iron-sulfur cluster proteins, ultimately leading to cell death
the genes CDKN2A, FDX1, DLD, DLAT, LIAS, GLS, LIPT1, MTF1, PDHA1 and PDHB are closely associated with cuproptosis as a form of mortality
one of the causes of cell death is the depletion of pyrimidines
PDHA1
Pyruvate Dehydrogenase E1 Subunit Alpha 1, abbreviated as PDHA1, is a protein-encoded gene, and diseases associated with PDHA1 include pyruvate dehydrogenase E1-alpha deficiency and sudden infant death syndrome
PDHA1 is able to achieve consistent prostate cancer development in human xenograft tumor models by affecting lipid synthesis
lysine acetylation of PDHA1 and PDP1 is very common in both epidermal growth factor (EGF)-stimulated cells and various human cancer cells, and that acetylation of K202 is able to inhibit PDP1 by dissociating its fifth PDHA1, both of which have a great role in promoting glycolysis and tumor development in cancer cells
the KEGG pathway of PDHA1 is mainly enriched in ERBB signaling pathway, pyrimidine metabolism, ribosome and spliceosome
CDKN2A
Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) is a protein-encoded gene and diseases associated with CDKN2A include melanoma, cutaneous malignancies 2 and melanoma-pancreatic cancer syndrome
mutation of CDKN2A gene is an important factor for pancreatic cancer tumorigenesis
along with PDHA1 may be used as a marker of osteosarcoma 2)
the GO entries of CDKN2A are mainly enriched in phagocytosis, translation initiation and T-cell receptor complex entries