skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: Cobalt amine complexes and Ru265 interact with the DIME region of the mitochondrial calcium uniporter
We report our investigation into the MCU-inhibitory activity of Co 3+ complexes in comparison to Ru265. These compounds reversibly inhibit the MCU with nanomolar potency. Mutagenesis studies and molecular docking simulations suggest that the complexes operate through interactions with the DIME motif of the MCU pore.  more » « less
Award ID(s):
1750295
PAR ID:
10330981
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Chemical Communications
Volume:
57
Issue:
50
ISSN:
1359-7345
Page Range / eLocation ID:
6161 to 6164
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; (, ChemMedChem)
    Abstract The mitochondrial calcium uniporter (MCU) is a transmembrane protein that is responsible for mediating mitochondrial calcium (mCa2+) uptake. Given this critical function, the MCU has been implicated as an important target for addressing various human diseases. As such, there has a been growing interest in developing small molecules that can inhibit this protein. To date, metal coordination complexes, particularly multinuclear ruthenium complexes, are the most widely investigated MCU inhibitors due to both their potent inhibitory activities as well as their longstanding use for this application. Recent efforts have expanded the metal‐based toolkit for MCU inhibition. This concept paper summarizes the development of new metal‐based inhibitors of the MCU and their structure‐activity relationships in the context of improving their potential for therapeutic use in managing human diseases related tomCa2+dysregulation. 
    more » « less
  2. ; (, European Journal of Inorganic Chemistry)
    Abstract The mitochondrial calcium uniporter (MCU) mediates uptake of calcium ions (Ca2+) into the mitochondria, a process that is vital for maintaining normal cellular function. Inhibitors of the MCU, the most promising of which are dinuclear ruthenium coordination compounds, have found use as both therapeutic agents and tools for studying the importance of this ion channel. In this study, six Co3+cage compounds with sarcophagine‐like ligands were assessed for their abilities to inhibit MCU‐mediated mitochondrial Ca2+uptake. These complexes were synthesized and characterized according to literature procedures and then investigated in cellular systems for their MCU‐inhibitory activities. Among these six compounds, [Co(sen)]3+(3, sen=5‐(4‐amino‐2‐azabutyl)‐5‐methyl‐3,7‐diaza‐1,9‐nonanediamine) was identified to be a potent MCU inhibitor, with IC50values of inhibition of 160 and 180 nM in permeabilized HeLa and HEK293T cells, respectively. Furthermore, the cellular uptake of compound3was determined, revealing moderate accumulation in cells. Most notably,3was demonstrated to operate in intact cells as an MCU inhibitor. Collectively, this work presents the viability of using cobalt coordination complexes as MCU inhibitors, providing a new direction for researchers to investigate. 
    more » « less
  3. ; ; ; ; (, Angewandte Chemie International Edition)
    Abstract The mitochondrial calcium uniporter (MCU) is the ion channel that mediates Ca2+uptake in mitochondria. Inhibitors of the MCU are valuable as potential therapeutic agents and tools to study mitochondrial Ca2+. The best‐known inhibitor of the MCU is the ruthenium compound Ru360. Although this compound is effective in permeabilized cells, it does not work in intact biological systems. We have recently reported the synthesis and characterization of Ru265, a complex that selectively inhibits the MCU in intact cells. Here, the physical and biological properties of Ru265 and Ru360 are described in detail. Using atomic absorption spectroscopy and X‐ray fluorescence imaging, we show that Ru265 is transported by organic cation transporter 3 (OCT3) and taken up more effectively than Ru360. As an explanation for the poor cell uptake of Ru360, we show that Ru360 is deactivated by biological reductants. These data highlight how structural modifications in metal complexes can have profound effects on their biological activities. 
    more » « less
  4. ; ; (, Genes)
    Obesity is a public health crisis, and its prevalence disproportionately affects African Americans in the United States. Dysregulation of organelle calcium homeostasis is associated with obesity. The mitochondrial calcium uniporter (MCU) complex is primarily responsible for mitochondrial calcium homeostasis. Obesity is a multifactorial disease in which genetic underpinnings such as single-nucleotide polymorphisms (SNPs) may contribute to disease progression. The objective of this study was to identify genetic variations of MCU with anthropometric measurements and obesity in the All of Us Research Program. Methods: We used an additive genetic model to assess the association between obesity traits (body mass index (BMI), waist and hip circumference) and selected MCU SNPs in 19,325 participants (3221 normal weight and 16,104 obese). Eleven common MCU SNPs with a minor allele frequency ≥ 5% were used for analysis. Results: We observed three MCU SNPs in self-reported Black/African American (B/AA) men, and six MCU SNPs in B/AA women associated with increased risk of obesity, whereas six MCU SNPs in White men, and nine MCU SNPs in White women were protective against obesity development. Conclusions: This study found associations of MCU SNPs with obesity, providing evidence of a potential predictor of obesity susceptibility in B/AA adults. 
    more » « less
  5. ; ; (, Angewandte Chemie International Edition)
    Abstract Inhibitors of the mitochondrial calcium uniporter (MCU) are valuable tools for studying the role of mitochondrial Ca2+in various pathophysiological conditions. In this study, a new fluorogenic MCU inhibitor,RuOCou, is presented. This compound is an analogue of the known MCU inhibitor Ru265 that contains fluorescent axial coumarin carboxylate ligands. Upon aquation ofRuOCouand release of the axial coumarin ligands, a simultaneous increase in its MCU‐inhibitory activity and fluorescence intensity is observed. The fluorescence response of this compound enabled its aquation to be monitored in both HeLa cell lysates and live HeLa cells. This fluorogenic prodrug represents a potential theranostic MCU inhibitor that can be leveraged for the treatment of human diseases related to MCU activity. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email