Journal Article Epublish
PubMed: 40443881 DOI: 10.1021/jacsau.5c00035
Copper Chelation Induces Morphology Change in Mitochondria of Triple-Negative Breast Cancer.
JACS Au 5(5):2102-2113
Authors: ChiaHung Lee, Zhen Xiao, Irene Lim, Ting Wang, Parisa Aghaei, Peter J Burke, Jianghong Rao
Affiliations
- Department of Biomedical Engineering, University of California, Irvine, California 92697, United States.
- Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, California 94305, United States.
- Department of Electrical Engineering and Computer Science, University of California, Irvine, California 92697, United States.
Abstract
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.
MeSH
Chelating Agents, Triple Negative Breast Neoplasms, Breast Neoplasms, Neoplasms, Mitochondria, Breast, Therapeutics