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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
PubMed

Insights

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.
Keywords:
Rho/MRTF/SRFacetylationbioenergeticshistone-4mitochondriaoxidative stress

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