Metabolic mysteries of copper dysregulation in Wilson disease

Abstract

Wilson disease, a well-established genetic disorder characterized by impaired copper excretion and toxic copper accumulation in the liver, has clear clinical presentations and diagnostic criteria. However, the metabolic and molecular pathways leading to liver injury - a critical hallmark of the disease - remain largely cryptic and require new analytical approaches to elucidate underlying mechanisms. In Wilson disease, supraphysiological and toxic amounts of hepatic copper arise due to genetically reduced biliary excretion. Interestingly, hepatic iron accumulation of unknown etiology is also observed. Both metals contribute to the production of reactive oxygen species (ROS), including singlet oxygen, superoxide anions, and highly disruptive hydroxyl radicals generated via the Haber-Weiss and Fenton reactions. Historically, liver injury has been attributed to copper-induced toxicity (cuproptosis) without sufficient consideration of ROS involvement, neglecting the significant ROS burden in hepatic tissue. A revised concept of cuproptosis incorporates ROS, particularly hydroxyl radicals, which convert copper ions into reactive intermediates such as copper peroxyl, copper hydroperoxyl, and copper superoxyl species. These intermediates induce mitochondrial oxidative stress by covalently binding to mitochondrial constituents including lipoylated dihydrolipoamide S-acetyltransferase (DLAT), leading to its aggregation and triggering regulated cell death via cuproptosis. Thus, copper ions must first be converted into reactive intermediates to initiate cuproptosis effectively. Furthermore, singlet oxygen and superoxide anion hydroxyl radicals generated by hepatic iron ions may promote regulated cell death via ferroptosis. This process involves the accumulation of lipid peroxides derived from polyunsaturated fatty acids in mitochondrial membranes, with malondialdehyde (MDA) serving as a diagnostic marker. Consequences include enhanced mitochondrial membrane rigidity, disruption of plasma membrane integrity, and ultimately cell death. This mechanistic pathway requires the activity of iron-dependent enzymes such as lipoxygenases, ferroptosis suppressor protein 1, glutathione peroxidase 4, dihydroorotate dehydrogenase, and lysosomal iron release from ferritin stores. To sum up, the definition of cuproptosis requires refinement to incorporate its mechanistic dependence on ROS, and its quantitative contribution to liver injury should be reassessed alongside hepatic iron and ferroptosis.

Keywords

Copper / Wilson disease / cuproptosis / ferroptosis / reactive oxygen species / immune reactions

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