Copper ionophore elicits calpain-dependent paraptosis coincident with proteotoxic stress

Abstract 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. Graphical abstract