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A Small-Molecule Inhibitor of Bax and Bak Oligomerization Prevents Genotoxic Cell Death and Promotes Neuroprotection

Xin Niu1, Hetal Brahmbhatt2, Philipp Mergenthaler3

  • 1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Cell Chemical Biology
|April 11, 2017
PubMed

Insights

Scientists discovered small molecules that inhibit Bax/Bak protein oligomerization, a key step in apoptosis. These inhibitors prevent mitochondrial outer membrane permeabilization (MOMP) and protect cells, offering potential treatments for degenerative diseases.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Pharmacology

Background:

  • Aberrant apoptosis contributes to acute and chronic degenerative diseases.
  • Mitochondrial outer membrane permeabilization (MOMP) is an irreversible apoptosis execution step, triggered by Bax/Bak protein oligomerization.
  • Targeting Bax/Bak oligomerization presents a therapeutic strategy for controlling apoptosis.

Purpose of the Study:

  • To discover and characterize small-molecule inhibitors of Bax/Bak oligomerization.
  • To investigate the mechanism by which these inhibitors prevent MOMP.
  • To evaluate the therapeutic potential of inhibiting Bax/Bak oligomerization in cellular models of neurodegeneration.

Main Methods:

  • High-throughput screening for small-molecule inhibitors of Bax/Bak oligomerization.
  • Biochemical assays to assess disruption of Bax dimer interfaces and higher-order oligomer formation.
  • Cell-based assays to evaluate protection against apoptotic stimuli and excitotoxicity in neuronal models.

Main Results:

  • Discovery of novel small molecules that inhibit Bax/Bak oligomerization.
  • Demonstrated that inhibitors interfere with Bax dimer interactions, preventing higher-order oligomer formation at the MOM.
  • Inhibitors prevented MOMP, allowed cells to evade apoptosis, and rescued neurons from excitotoxicity-induced death.

Conclusions:

  • Bax/Bak oligomerization is essential for MOMP.
  • Small-molecule Bax/Bak inhibitors are effective tools for studying MOMP mechanisms.
  • These inhibitors hold promise for developing new treatments for acute and chronic degenerative diseases by modulating apoptosis.
Keywords:
BakBaxBcl-2 familyapoptosisexcitotoxicitymitochondrial outer membrane permeabilizationprogrammed cell deathsmall-molecule inhibitors

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