Exploring copper metabolism and cuproptosis, and their implications in ocular diseases

Copper is a vital trace element for all living organisms and plays an important role in numerous physiological functions, including the formation of mitochondrial respiratory chain complexes, antioxidant defense, and signal transduction. However, excess copper can cause cellular toxicity and initiate a form of cell death that is characterized by the aggregation of lipoylated proteins and a reduction in Fe-S cluster proteins. This series of events can culminate in mitochondrial process of respiratory dysfunction known as cuproptosis. Excessive copper can also inhibit the ubiquitin-proteasome system, which results in the accumulation of harmful proteins and a vicious cycle of Fenton and Haber-Weiss reactions that trigger oxidative stress and cellular damage. The eye, particularly the retina, is one of the most energy-dependent tissues in the body and has an extraordinary dependence on mitochondrial function. Dysregulated copper-ion levels can lead to mitochondrial dysfunction, which can cause various ocular diseases, including uveal melanoma, age-related macular degeneration, and diabetic retinopathy. Therefore, the relationship between copper and ocular diseases provides promising research opportunities. This review summarizes recent research findings on copper metabolism, cuproptosis, and their implications in ocular diseases. It also introduces potential therapeutic approaches for related diseases, including copper chelation therapy, copper ionophores and nanomedicine, and genetic treatment strategies.