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Inhibitors of Rho/MRTF/SRF Transcription Pathway Regulate Mitochondrial Function
Pankaj Patyal1, Xiaomin Zhang1, Ambika Verma1
1Donald W. Reynolds Department of Geriatrics and Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Cells
|March 13, 2024
Summary
Novel oxadiazole-thioether compounds, CCG-203971 and CCG-232601, inhibit Rho/MRTF/SRF signaling. These compounds target mitochondrial function by altering gene expression, offering potential therapeutic strategies for diseases involving aberrant bioenergetics.
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- The RhoA/SRF/MRTFs pathway is a key regulator of gene transcription and a therapeutic target for various diseases.
- Mitochondrial dysfunction and altered metabolism are hallmarks of cancer, presenting a vulnerability for targeted therapies.
- Novel oxadiazole-thioether compounds disrupt SRF transcription, but their precise molecular targets and mechanisms remain unclear.
Purpose of the Study:
- To elucidate the Rho/MRTF/SRF inhibition mechanism of CCG-203971 and CCG-232601.
- To investigate the role of these compounds in targeting mitochondrial function and bioenergetics.
- To explore the therapeutic potential of these molecules in diseases characterized by aberrant cellular metabolism.
Main Methods:
- Utilized normal human lung fibroblasts and mouse myoblasts to study Rho/MRTF/SRF inhibition.
- Investigated the effects of CCG-203971 and CCG-232601 on histone modifications, specifically H4K12 and H4K16 acetylation.
- Analyzed gene expression related to mitochondrial function and dynamics.
- Assessed the impact of the compounds on mitochondrial electron transport chain complexes and cellular respiration.
Main Results:
- CCG-203971 and CCG-232601 were demonstrated to inhibit the Rho/MRTF/SRF signaling pathway.
- These compounds induce hyperacetylation of histone H4K12 and H4K16, regulating genes involved in mitochondrial function and dynamics.
- The inhibitors repress oxidative phosphorylation, increase glycolysis, inhibit all mitochondrial electron transport chain complexes, and induce oxidative stress.
- These effects suggest a compensatory mechanism to regulate mitochondrial function.
Conclusions:
- CCG-203971 and CCG-232601 effectively inhibit Rho/MRTF/SRF signaling and target mitochondrial bioenergetics.
- The compounds' ability to induce oxidative stress and alter metabolic pathways highlights their therapeutic potential.
- These findings suggest a promising strategy for targeting aberrant bioenergetics in diseases like cancer.
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