Copper induces cell death by targeting lipoylated TCA cycle proteins

  • Science. 2022 Mar 18;375(6586):1254-1261. doi: 10.1126/science.abf0529.
Peter Tsvetkov  1 ,  Shannon Coy  2  3  4  5 ,  Boryana Petrova  5  6 ,  Margaret Dreishpoon  1 ,  Ana Verma  2  3  4  5 ,  Mai Abdusamad  1 ,  Jordan Rossen  1 ,  Lena Joesch-Cohen  1 ,  Ranad Humeidi  1 ,  Ryan D Spangler  1 ,  John K Eaton  1 ,  Evgeni Frenkel  7 ,  Mustafa Kocak  1 ,  Steven M Corsello  1  5  8 ,  Svetlana Lutsenko  9 ,  Naama Kanarek  1  5  6 ,  Sandro Santagata  2  3  4  5  10 ,  Todd R Golub  1  5  11  12
Affiliations
  • 1. Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 2. Laboratory of Systems Pharmacology, Department of Systems Biology, Boston, MA, USA.
  • 3. Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
  • 4. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
  • 5. Harvard Medical School, Boston, MA, USA.
  • 6. Department of Pathology, Boston Children's Hospital, Boston, MA USA.
  • 7. Whitehead Institute and Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 8. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
  • 9. Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD, USA.
  • 10. Department of Pathology, Dana Farber Cancer Institute, Boston, MA, USA.
  • 11. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
  • 12. Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
PMID: 35298263 DOI: 10.1126/science.abf0529
Abstract

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.

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