Copper-Induced Oxidative Stress and Cell Death Mechanisms

Copper is an indispensable trace element, serving as a cofactor for enzymes involved in respiration, antioxidant defence and neurotransmitter synthesis. However, its redox activity renders it capable of catalysing Fenton-type reactions, yielding reactive oxygen species (ROS) that damage lipids, proteins and nucleic acids. When cellular antioxidant systems—such as glutathione, superoxide dismutase and catalase—are overwhelmed, oxidative stress ensues. Prolonged or excessive copper exposure can engage multiple cell-death pathways. Classical apoptosis is triggered via mitochondrial membrane depolarisation, cytochrome c release and caspase activation. Autophagy may be initially protective but can transition into autophagic cell death when organelle clearance is excessive or dysregulated. More recently, a distinct copper-dependent mechanism termed cuproptosis has been defined. This process involves direct binding of copper to lipoylated mitochondrial enzymes, leading to aggregation of protein complexes, loss of iron–sulphur cluster proteins and proteotoxic stress. In parallel, copper can induce epithelial–mesenchymal transition in parenchymal cells, contributing to fibrotic remodelling in organs such as the lung and liver. The intersection of these pathways underlies the pathology of neurodegenerative disorders, hepatic and renal toxicity, and fibrotic disease linked to environmental, occupational or dietary copper overload. Understanding the regulatory networks that balance copper uptake, sequestration and export is crucial to devise interventions that mitigate oxidative injury while preserving essential metalloenzyme function.

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Copper-Induced Oxidative Stress and Cell Death Mechanisms publication trend

The graph below shows the total number of articles in copper-induced oxidative stress and cell death mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can oxidise cellular components.

Apoptosis: Programmed cell death involving mitochondrial permeabilisation, caspase activation and DNA fragmentation.

Autophagy: Lysosomal degradation pathway of damaged organelles and proteins, which can be protective or lead to cell death if excessive.

Cuproptosis: Copper-dependent form of regulated cell death marked by aggregation of lipoylated mitochondrial proteins and loss of iron–sulphur cluster proteins.

Epithelial–mesenchymal transition (EMT): Phenotypic conversion of epithelial cells into migratory mesenchymal cells, contributing to fibrosis.

Nrf2: Transcription factor that orchestrates the expression of antioxidant and cytoprotective genes.

Keap1: Cytosolic regulator that binds Nrf2 under basal conditions, targeting it for ubiquitin-mediated degradation.

References

1. CircSpna2 attenuates cuproptosis by mediating ubiquitin ligase Keap1 to regulate the Nrf2‐Atp7b signalling axis in depression after traumatic brain injury in a mouse model. Clinical and Translational Medicine (2024).
2. Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human. Antioxidants (2023).
3. Copper Induces Cognitive Impairment in Mice via Modulation of Cuproptosis and CREB Signaling. Nutrients (2023).