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

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abstract

  • Aberrant apoptosis can lead to acute or chronic degenerative diseases. Mitochondrial outer membrane permeabilization (MOMP) triggered by the oligomerization of the Bcl-2 family proteins Bax/Bak is an irreversible step leading to execution of apoptosis. Here, we describe the discovery of small-molecule inhibitors of Bax/Bak oligomerization that prevent MOMP. We demonstrate that these molecules disrupt multiple, but not all, interactions between Bax dimer interfaces thereby interfering with the formation of higher-order oligomers in the MOM, but not recruitment of Bax to the MOM. Small-molecule inhibition of Bax/Bak oligomerization allowed cells to evade apoptotic stimuli and rescued neurons from death after excitotoxicity, demonstrating that oligomerization of Bax is essential for MOMP. Our discovery of small-molecule Bax/Bak inhibitors provides novel tools for the investigation of the mechanisms leading to MOMP and will ultimately facilitate development of compounds inhibiting Bax/Bak in acute and chronic degenerative diseases.

authors

  • Niu, Xin
  • Brahmbhatt, Hetal
  • Mergenthaler, Philipp
  • Zhang, Zhi
  • Sang, Jing
  • Daude, Michael
  • Ehlert, Fabian GR
  • Diederich, Wibke E
  • Wong, Eve
  • Zhu, Weijia
  • Pogmore, Justin
  • Nandy, Jyoti P
  • Satyanarayana, Maragani
  • Jimmidi, Ravi K
  • Arya, Prabhat
  • Leber, Brian
  • Lin, Jialing
  • Culmsee, Carsten
  • Yi, Jing
  • Andrews, David W

publication date

  • April 2017

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