Abstract
Mitochondrial structure and organization is integral to maintaining mitochondrial homeostasis and an emerging biological target in aging, inflammation, neurodegeneration, and cancer. The study of mitochondrial structure and its functional implications remains challenging in part because of the lack of available tools for direct engagement, particularly in a disease setting. Here, we report a gold-based approach to perturb mitochondrial structure in cancer cells. Specifically, the design and synthesis of a series of tricoordinate Au(I) complexes with systematic modifications to group 15 nonmetallic ligands establish structure-activity relationships (SAR) to identify physiologically relevant tools for mitochondrial perturbation. The optimized compound, AuTri-9 selectively disrupts breast cancer mitochondrial structure rapidly as observed by transmission electron microscopy with attendant effects on fusion and fission proteins. This phenomenon triggers severe depolarization of the mitochondrial membrane in cancer cells. The high in vivo tolerability of AuTri-9 in mice demonstrates its preclinical utility. This work provides a basis for rational design of gold-based agents to control mitochondrial structure and dynamics.
| Original language | English |
|---|---|
| Pages (from-to) | 439-449 |
| Number of pages | 11 |
| Journal | JACS Au |
| Volume | 1 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 26 2021 |
Bibliographical note
Funding Information:We would like to thank all of the facilities at the University of Kentucky who provided support in completion of the experiments detailed in this manuscript. The UK NMR Center supported by NSF (CHE997738) and the UK X-ray facility supported by the MRI program from NSF (CHE-1625732). For the flow cytometry experiments, we would like to thank Greg Bauman PhD (UK Flow Cytometry and Immune Function core supported by the Office of the Vice President of Research, the Markey Cancer Center, and NCI Center Core Support Grant (P30 CA177558). For microscopy, we would like to thank Dr. Thomas Wilkop and Mr. James Schwartz (UK Light Microscopy Core) for their assistance. We would also like to thank Dr. Tomoko Sengoku and Mr. Michael Alstott for the support with our redox metabolism experiments, supported by the shared resources of the University of Kentucky Markey Cancer Center (P30CA177558). We would also like to acknowledge Jim Begley for the preparation of TEM samples, located in the Jacob’s Science Building, College of Arts and Science, Lexington, KY. Establishment of prep services was made possible through partial support from the Office of the VPR. TEM analysis was conducted at the electron microscopy center (EMC) which belongs to the National Science Foundation NNCI Kentucky Multiscale Manufacturing and Nano Integration Node, supported by ECCS-1542174.
Funding Information:
We are grateful to the University of Kentucky and Oberlin College for funding. The authors acknowledge support from the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456) and the Oberlin College Office of Foundation, Government and Corporate Grants (Grant-in-Aid to Gunnar F. Kwakye)
Publisher Copyright:
© 2021 American Chemical Society. All rights reserved.
Keywords
- anticancer
- biogenesis
- breast cancer
- chemical probe
- gold compounds
- mitochondria
- structure
ASJC Scopus subject areas
- Chemistry (miscellaneous)
- Analytical Chemistry
- Organic Chemistry
- Physical and Theoretical Chemistry
