Copper induces cell death by targeting lipoylated TCA cycle proteins
Copper induces cell death
Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al. investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK
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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Correction 22 April 2022:
Table S2 should have contained the underlying data for the genetic modifier screens using both native disulfiram and its active, copper-loaded form, cupric-DDC. The table has therefore been updated to include the complete dataset. Captions have also been added for tables S1 to S5. The original version is available here:
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Volume 375 | Issue 6586
18 March 2022
18 March 2022
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Received: 30 September 2020
Accepted: 4 February 2022
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Acknowledgments
We thank J. Markley, H. Adelmann, M. Slabicki, V. Wang, and H. Keys for constructive discussion and help with genetic screens. We thank T. Woo for help with immunohistochemistry and immunofluorescence studies and A. Muchenditsi for help with the Atp7b mice. We thank C. Lewis (Whitehead metabolomics), W. Salmon (Whitehead imaging), and R. Rodrigues (Harvard Medical School–Thermo Fisher Scientific Center for Multiplexed Proteomics proteomic facility) for technical help. We thank M. O’Reilly for help with the design of the figures. We thank the Image and Data Analysis Core at Harvard Medical School for coding support.
Funding: This work was supported by National Cancer Institute (NCI) grant 1 R35 CA242457-01 (T.R.G.), Novo Holdings (T.R.G. and P.T.), NCI grant K08 CA230220 (S.M.C.), National Institute of General Medical Sciences grant T32-GM007748 (S.C.), research and recruitment funding by Boston Children’s Hospital (B.P. and N.K.), NCI grant R01-CA194005, NCI grant U54-CA225088, and the Ludwig Center at Harvard (S.S.).
Author contributions: P.T. conceptualized the project, conducted experiments, collected data, and analyzed results. M.A. and M.D. assisted with experiments. L.J.-C., J.R., and M.K. assisted with data analysis. R.H. and R.D.S. performed the whole-genome CRISPR-Cas9 screens under supervision from S.M.C. S.C. and S.S. performed the tissue microarray staining scoring and visualization, and A.V. assisted with the microscopy analysis. B.P. and N.K. performed and analyzed the metabolomics experiments. S.L. provided study material and experimental advice. J.K.E. and E.F. provided reagents and experimental advice. T.R.G. supervised the research. P.T. and T.R.G. wrote the manuscript.
Competing interests: S.M.C. and T.R.G. receive research funding unrelated to this project from Bayer HealthCare and Calico Life Sciences. T.R.G. receives research funding related to this project from Novo Holdings, recently held equity in FORMA Therapeutics, is a consultant to GlaxoSmithKline and Anji Pharmaceuticals, and is a founder of Sherlock Biosciences. S.S. is a consultant for RareCyte, Inc. P.T. and T.R.G. are inventors on the patent application PCT/US21/19871 submitted by the Broad Institute entitled “Method of treating cancer.” J.E. is currently an employee of Kojin Therapeutics. The other authors declare no competing interests.
Data and materials availability: All data are available in the manuscript or the supplementary materials.
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National Cancer Institute: R35 CA242457-01
National Cancer Institute: K08 CA230220
National Cancer Institute: R01-CA194005
National Cancer Institute: U54-CA225088
Ludwig Center at Harvard Medical School
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Cuproptosis: A new potential therapeutic target of glioma
Many thanks to Tsvetkov et al. for creatively proposing the concept of cuproptosis in the article “Copper induces cell death by targeting lipoylated TCA cycle proteins”[1] It is a completely new way of cell death, independent of the common apoptosis, necroptosis, ferroptosis, oxidative stress, which causes cell death by influencing the TCA cycle. Before this, copper was loaded with nanoparticles to produce ROS to kill glioma cells[2][3][4][5] or to interact with TMZ to kill glioma[6]. We believe the view in this article is clear, however, some prospects and issues still need to be discussed.
Firstly, FDX1 is mentioned as a necessary factor for cuproptosis, which encodes a reductase known to reduce Cu2+ to its more toxic form, Cu1+. We noticed that FDX1 in the TCGA database is highly expressed in many cancers, especially glioblastoma multiforme. It can be a potential new target fight against glioblastoma
Whatsmore, the strong connection between copper-mediated cell death and both FDX1 expression and protein lipoylation was lost at high concentrations of elesclomol suggesting another mechanism more than protein lipoylation.
All in all, we admire the author's relevant findings on cuproptosis, by targeting lipoylated TCA cycle proteins. There is no doubt that there are still some hidden mechanisms that have not been mined. But it still broadens our horizon for our understanding of copper-mediated glioma treatment.
Reference:
[1] P. Tsvetkov et al., “Copper induces cell death by targeting lipoylated TCA cycle proteins,” Science (80-. )., vol. 375, no. 6586, pp. 1254–1261, 2022, doi: 10.1126/science.abf0529.
[2] C. Rae, M. Tesson, J. W. Babich, M. Boyd, A. Sorensen, and R. J. Mairs, “The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells,” J. Nucl. Med., vol. 54, no. 6, pp. 953–960, Jun. 2013, doi: 10.2967/JNUMED.112.113324.
[3] K. Shimada et al., “Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells,” Cell Chem. Biol., vol. 25, no. 5, pp. 585-594.e7, May 2018, doi: 10.1016/J.CHEMBIOL.2018.02.010.
[4] Q. H. Lan et al., “Disulfiram-loaded copper sulfide nanoparticles for potential anti-glioma therapy,” Int. J. Pharm., vol. 607, Sep. 2021, doi: 10.1016/J.IJPHARM.2021.120978.
[5] M. Buccarelli et al., “Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth,” J. Exp. Clin. Cancer Res., vol. 40, no. 1, pp. 1–17, 2021, doi: 10.1186/s13046-021-02031-4.
[6] X. Li, F. Shao, J. Sun, K. Du, Y. Sun, and F. Feng, “Enhanced Copper-Temozolomide Interactions by Protein for Chemotherapy against Glioblastoma Multiforme,” ACS Appl. Mater. Interfaces, 2019, doi: 10.1021/acsami.9b14849.
Some Opinions and Prospects about Cuproptosis
In their excellent article “Copper induces cell death by targeting lipoylated TCA cycle proteins”, Tsvetkov et al. [1] challenged traditional cell death dogma and proposed that excessive copper sedimentation caused cell death by impairing mitochondrial metabolism, namely cuproptosis. Interestingly, we also found copper overload disturbed the mitochondria metabolism in nontumoral, mitochondria-rich renal tubular epithelial cells (RTECs). We believe the view in this article are clear, however, there are some issues need to be discussed.
Firstly, cuproptosis in this article was induced by pulse treatment with Cu2+ ionophore elesclomol, causing 15- to 60-fold increase of intracellular copper and then triggering cell death [1]. However, Cu1+, not Cu2+, are transported into cells by high-affinity copper uptake protein (CTR1) under physiological conditions [2]. We proved that CTR1 was highly expressed in RTECs under pathophysiological situations[3], and the mitochondrial cooper levels were increased about 1.5- to 2-fold. Pretreatment of the cell with tetrathiomolybdate (TM), a copper chelation agent, markedly restored the deformation of mitochondria and the reduction in mitochondrial membrane potential（MMP） induced by pathogenic TGF-β1 or CuSO4 treatment. Our results suggest that mild accumulation of copper ions was able to trigger cell damage.
Furthermore, the authors revealed excess copper promoted lipoylated protein aggregation and iron-sulfur cluster protein loss in tricarboxylic acid cycle, not directly affected mitochondrial respiratory chain [1]. But in our observations the result showed that copper overload directly disrupted the activity of respiratory chain complex IV, which is the only complex that activated by combining with copper in respiratory chain. Our results suggest that mild copper accumulation in RTECs is enough to impair the complex IV activity and induce mitochondria dysfunction.
In summary, we admired the fundamental discovery of the paper that revealed a novel cell death mode, the cuproptosis. Affecting lipoylated components of the tricarboxylic acid cycle was implicated in cuproptosis with no doubt, but still there were other issues in cuproptosis remained to be clarified. Impairing the activity of complex IV might be another node for initiating cuproptosis.
Reference: