2022/03/17 by Peter Tsvetkov, Shannon Coy, Boryana Petrova +15 · 21 citations
Biochemistry, Genetics and Molecular Biology · Medicine · Nursing · #Alzheimer's disease research and treatments #Mitochondrial Function and Pathology #Trace Elements in Health
paper · doi:10.1126/science.abf0529
openalex publication_date 2022/03/17 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.