Copper induces cell death by targeting lipoylated TCA cycle proteins

Science. 2022 Mar 18;375(6586):1254-1261. doi: 10.1126/science.abf0529. Epub 2022 Mar 17.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Respiration
  • Citric Acid Cycle*
  • Copper / metabolism*
  • Copper / toxicity*
  • Dihydrolipoyllysine-Residue Acetyltransferase / metabolism
  • Hepatolenticular Degeneration / metabolism
  • Homeostasis
  • Humans
  • Hydrazines / toxicity
  • Ionophores / toxicity
  • Iron-Sulfur Proteins / metabolism
  • Lipoylation
  • Metabolic Networks and Pathways
  • Mice
  • Mitochondria / metabolism
  • Regulated Cell Death*


  • Hydrazines
  • Ionophores
  • Iron-Sulfur Proteins
  • elesclomol
  • Copper
  • Dihydrolipoyllysine-Residue Acetyltransferase