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Copper induces cell death by targeting lipoylated TCA cycle proteins

Peter TsvetkovBroad Institute of Harvard and MIT, Cambridge, MA, USAShannon CoyDepartment of Pathology, Brigham and Women’s Hospital, Boston, MA, USABoryana PetrovaDepartment of Pathology, Boston Children’s Hospital, Boston, MA USAMargaret DreishpoonBroad Institute of Harvard and MIT, Cambridge, MA, USAAna VermaDepartment of Pathology, Brigham and Women’s Hospital, Boston, MA, USAMai AbdusamadBroad Institute of Harvard and MIT, Cambridge, MA, USAJordan RossenBroad Institute of Harvard and MIT, Cambridge, MA, USALena Joesch-CohenBroad Institute of Harvard and MIT, Cambridge, MA, USARanad HumeidiBroad Institute of Harvard and MIT, Cambridge, MA, USARyan D. SpanglerBroad Institute of Harvard and MIT, Cambridge, MA, USAJohn K. EatonBroad Institute of Harvard and MIT, Cambridge, MA, USAEvgeni M. FrenkelWhitehead Institute and Massachusetts Institute of Technology, Cambridge, MA, USAMustafa KocakBroad Institute of Harvard and MIT, Cambridge, MA, USASteven M. CorselloBroad Institute of Harvard and MIT, Cambridge, MA, USASvetlana LutsenkoDepartment of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD, USANaama KanarekBroad Institute of Harvard and MIT, Cambridge, MA, USASandro SantagataDepartment of Pathology, Brigham and Women’s Hospital, Boston, MA, USATodd R. GolubBroad Institute of Harvard and MIT, Cambridge, MA, USA

2022en

ABI

Annotatsiya

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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DOI: 10.1126/science.abf0529

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