Copper Chelation Induces Morphology Change in Mitochondria of Triple-Negative Breast Cancer

Recent studies implicate mitochondria playing a key role in the cellular response to copper depletion therapy; however, evidence has been indirect and downstream, and the initial target of chelation remains to be defined. Here, we show, using super-resolution voltage and structure imaging microscopy, that copper chelation directly affects mitochondria morphology (causing fragmentation of the filamentous network) and ultrastructure (causing internal cristae remodeling). When triple-negative breast cancer cells are treated with a mitochondria-targeting copper chelator, mitochondria undergo an irreversible change in morphology from tubular to spherical. This process can be prevented by the addition of exogenous copper during the treatment. We find that a tailor-designed chelating agent with positive charges to target mitochondrial electrostatics localizes inside the mitochondrial cristae in a voltage-dependent manner. On pharmacological induction of membrane potential collapse, the chelator is dispersed while the mitochondrial cristae structure is preserved. These results indicate that voltage-dependent localization/targeting of the copper chelator in mitochondrial cristae plays a key role in its cytotoxicity.