Cuproptosis: The Hidden Impact of Copper-Induced Cell Death

Cells rely on precise biochemical balance to function properly, and disruptions in metal homeostasis can have profound effects. While copper is an essential trace element, excessive accumulation triggers a newly characterized form of cell death called cuproptosis. Unlike other regulated cell death mechanisms, cuproptosis is directly linked to mitochondrial metabolism and protein aggregation.

Understanding this process is crucial because copper dysregulation plays a role in diseases such as cancer and neurodegenerative disorders. Researchers are now exploring how targeting cuproptosis could lead to novel therapeutic strategies.

Key Biochemical Steps

Cuproptosis begins when intracellular copper levels exceed a threshold that disrupts normal metabolism. Unlike oxidative stress-driven cell death, this process is specifically tied to mitochondrial function. The primary trigger is copper binding to lipoylated components of the tricarboxylic acid (TCA) cycle, particularly enzymes like dihydrolipoamide S-acetyltransferase (DLAT). This interaction leads to protein aggregation, impairing enzymatic activity and mitochondrial respiration.

As copper-bound proteins accumulate, they interfere with the electron transport chain, causing metabolic dysfunction. Disrupting oxidative phosphorylation alters NADH/NAD+ ratios, increasing cellular stress. The aggregation of lipoylated proteins also overwhelms the cell’s ability to degrade misfolded proteins, creating toxicity that drives the cell toward collapse.

A key distinction of cuproptosis is its dependence on mitochondrial integrity, unlike apoptosis or ferroptosis. Cells reliant on oxidative metabolism, such as those in the heart and liver, are particularly vulnerable. Studies show that cells with impaired mitochondrial function resist cuproptosis, emphasizing the necessity of an active TCA cycle. This specificity suggests that targeting mitochondrial metabolism could help regulate cuproptosis in therapeutic contexts.

Mitochondrial Iron-Sulfur Cluster Interaction

Disrupting mitochondrial iron-sulfur (Fe-S) cluster homeostasis is a critical step in cuproptosis. These clusters, composed of iron and sulfur atoms, are essential for electron transport and metabolic regulation. Their assembly and incorporation rely on the iron-sulfur cluster (ISC) machinery. When copper accumulation interferes with this system, mitochondrial stability and function deteriorate.

Excess copper disrupts Fe-S clusters by displacing iron within these cofactors. Because Cu(I) and Fe(II) have similar charge and coordination properties, copper outcompetes iron for binding sites, leading to cluster degradation. This damages electron transport chain complexes I, II, and III, increasing electron leakage and oxidative stress. The resulting mitochondrial dysfunction accelerates cuproptotic cell death.

Copper also interferes with ISC assembly, further depleting Fe-S clusters. Enzymes such as ISCU and NFS1, crucial for assembling these clusters, are highly sensitive to copper toxicity. Their inhibition weakens oxidative phosphorylation and impairs aconitase activity in the TCA cycle, exacerbating metabolic collapse. This reinforces the specificity of cuproptosis to mitochondrial metabolism.

Regulatory Proteins

Cuproptosis is controlled by regulatory proteins that manage copper transport, protein modification, and mitochondrial function. Copper chaperones such as ATOX1 and CCS distribute copper while preventing excess accumulation. When this system fails, unbound copper builds up in mitochondria, triggering cuproptotic cell death.

Protein modifications also influence mitochondrial susceptibility to copper toxicity. LIAS (lipoic acid synthetase) facilitates the lipoylation of metabolic enzymes, a modification essential for function but also a vulnerability to copper binding. Cells with reduced LIAS expression resist cuproptosis due to fewer lipoylated proteins available for copper interaction. Modulating LIAS activity could help control copper-induced cell death in disease contexts.

ATP7A and ATP7B, two P-type ATPases, regulate copper export to maintain cellular balance. Mutations in ATP7B, as seen in Wilson’s disease, impair copper clearance and heighten sensitivity to cuproptotic triggers. This highlights how genetic variations in copper-handling proteins influence susceptibility to cuproptosis, underscoring the need for personalized therapeutic approaches.

Disease Relevance

Copper homeostasis disruptions are implicated in various diseases, with cuproptosis offering a new perspective on copper toxicity. In some cancers, altered copper metabolism supports tumor progression, as malignant cells often increase copper uptake for rapid proliferation. Researchers are investigating whether inducing cuproptosis could selectively target cancer cells with high mitochondrial activity, offering a potential treatment strategy for therapy-resistant malignancies.

Neurodegenerative disorders also exhibit copper dysregulation, particularly in Alzheimer’s and Parkinson’s disease. Elevated copper levels in affected brain regions may contribute to protein misfolding and aggregation. While oxidative stress has long been considered a factor in neurodegeneration, cuproptosis suggests copper-induced mitochondrial dysfunction may play a more direct role in neuronal loss. Understanding how neurons regulate copper levels could inform new therapeutic strategies aimed at stabilizing copper balance before irreversible damage occurs.