2. Academic Validation
  3. Copper induces cell death by targeting lipoylated TCA cycle proteins

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

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.

Figures
Products