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Sae-Fung A, Fadeel B
Cell Commun Signal 24 (1) 47 [2025-12-12; online 2025-12-12]
Copper is essential to all living organisms. However, too much copper is deleterious, and cellular copper content is therefore subject to tight control. Excess copper was recently found to perturb a set of metabolic enzymes in mitochondria, leading to the aggregation of these proteins and the demise of the cell. However, our understanding of the mechanism of copper-dependent cell death remains incomplete. Here, we report that copper ionophore (elesclomol)-induced cell death is calpain-dependent, featuring dilation of the endoplasmic reticulum along with perinuclear clustering of mitochondria. Moreover, elesclomol evoked proteotoxic stress, manifested as a disruption of ubiquitin and proteasome homeostasis, coupled with a conserved heat shock response. Overall, these results have shown that elesclomol promotes calpain-dependent paraptosis with the involvement of both mitochondrial and extramitochondrial compartments of the cell.
PubMed 41388416
DOI 10.1186/s12964-025-02558-5
Crossref 10.1186/s12964-025-02558-5
pmc: PMC12837948
pii: 10.1186/s12964-025-02558-5