Synthetic Control of Mitochondrial Dynamics: Developing Three-Coordinate Au(I) Probes for Perturbation of Mitochondria Structure and Function

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.

Publisher

American Chemical Society

Publication Date

4-26-2021

Publication Title

JACS AU

Department

Neuroscience

Document Type

Article

DOI

https://dx.doi.org/10.1021/jacsau.1c00051

Keywords

Mitochondria, Gold compounds, Chemical probe, Structure, Anticancer, Breast cancer, Biogenesis

Language

English

Format

text

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