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.

Recent development of gold(i) and gold(iii) complexes as therapeutic agents for cancer diseases

“…This phenomenon induced severe depolarization of the mitochondrial membrane in cancer cells. 105 Galassi et al synthesized and characterized a series of novel phosphane gold( i ) complexes and screened them for antiproliferative activity including 114 and 115 in a series of cancer cell lines (SKBR3, A17, and MDA-MB-231). Among them, only those with the N-Au-P bond and no hydroxyl or carboxyl groups in the ligands were considered to be active.…”

Self-assembled ruthenium and osmium nanosystems display a potent anticancer profile by interfering with metabolic activity

“…104 Cationic gold (Au I and Au III ) complexes were also shown to accumulate in mitochondria and strongly alter mitochondrial structure and function, being particularly potent on aggressive breast cancer cell line. 21,105 All together, this suggests that metallodrugs bearing a positive charge and balanced lipophilicity can accumulate inside mitochondria, offering promising alternatives to tackle tumor cells via non-nuclear or genomic pathways.…”

“…[7][8][9] The success of platinum drugs has led to novel metal-based candidates and turned attention to neighboring transition elements. Among these, ruthenium, 10-12 osmium, 13,14 iridium, 15 rhodium, 16 titanium 17,18 rhenium, 19,20 and gold [21][22][23][24] are under study.…”

“…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 resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558). This research was partially funded by NCI R50 CA243706-02 for MON, NCI R01 CA258421-01 for SGA, by the Fédération Wallonie-Bruxelles (EG/MA/JCD/CBV [19][20][21][22][23][24] for M. M. and by the Belgian Brain Tumor Support (BBTS) for V. M.; G. B. was the recipient of an FRS-FNRS award.…”

Next Generation Gold Drugs and Probes: Chemistry and Biomedical Applications

“…(d) Immunoblots of OPA1, MFF, MFN1, and TOM20. Reproduced from ref . Copyright 2021 American Chemical Society.…”