Open AccessSynthetic Control of Mitochondrial Dynamics: Developing Three-Coordinate Au(I) Probes for Perturbation of Mitochondria Structure and Function
Author(s) -
Randall Tyler Mertens,
William C. Jennings,
Samuel Ofori,
Jong Hyun Kim,
Sean Parkin,
Gunnar F. Kwakye,
Samuel G. Awuah
Publication year - 2021
Publication title -
jacs au
Language(s) - English
Resource type - Journals
ISSN - 2691-3704
DOI - 10.1021/jacsau.1c00051
Subject(s) - mitochondrion , mitochondrial fusion , rational design , microbiology and biotechnology , neurodegeneration , biophysics , inner mitochondrial membrane , biology , mitochondrial permeability transition pore , chemistry , computational biology , biochemistry , disease , apoptosis , medicine , mitochondrial dna , programmed cell death , pathology , genetics , gene
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.