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Copper induces cell death by targeting lipoylated TCA cycle proteins

Peter TsvetkovBroad Institute of Harvard and MIT, Cambridge, MA, USAShannon CoyHarvard Medical School, Boston, MA, USABoryana PetrovaHarvard Medical School, Boston, MA, USAMargaret DreishpoonBroad Institute of Harvard and MIT, Cambridge, MA, USAAna VermaLaboratory of Systems Pharmacology, Department of Systems Biology, 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. CorselloHarvard Medical School, Boston, MA, USASvetlana LutsenkoDepartment of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD, USANaama KanarekDepartment of Pathology, Boston Children's Hospital, Boston, MA USASandro SantagataLaboratory of Systems Pharmacology, Department of Systems Biology, Boston, MA, USATodd R. GolubDivision of Pediatric Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA

2022en

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Manbada oʻqishwww.ncbi.nlm.nih.gov(yangi oynada ochiladi)

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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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