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VDAC blockage by phosphorothioate oligonucleotides and its implication in apoptosis

Wenzhi Tan1

  • 1Farber Institute for Neurosciences, Weinberg Unit for ALS Research, Thomas Jefferson University, Philadelphia, PA 19107, USA. wenzhi.tan@jefferson.edu

Biochimica Et Biophysica Acta
|January 13, 2012
PubMed

Insights

Voltage-dependent anion channel (VDAC) gating influences cytochrome c release and apoptosis. Blockage of VDAC by G3139, a phosphorothioate oligonucleotide, demonstrates VDAC

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Apoptosis is vital for multicellular organism homeostasis, with dysregulation implicated in cancer and neurodegenerative diseases.
  • The intrinsic apoptotic pathway involves cytochrome c release from mitochondria.
  • Voltage-dependent anion channel (VDAC) regulates metabolite flux across the mitochondrial outer membrane (MOM).

Purpose of the Study:

  • To review evidence linking VDAC gating and MOM permeability to cytochrome c release and apoptosis.
  • To highlight the role of VDAC in initiating apoptosis, particularly through its blockage.

Main Methods:

  • Review of recent research on VDAC conducting states and their influence on cytochrome c release.
  • Analysis of evidence for VDAC blockage by G3139, a phosphorothioate oligonucleotide, and its proapoptotic activity.
  • Examination of shared characteristics between VDAC blockage and proapoptotic activity of G3139.

Main Results:

  • VDAC gating and subsequent changes in MOM permeability influence cytochrome c release and apoptosis.
  • Blockage of VDAC by G3139 provides strong evidence for VDAC's role in initiating apoptosis.
  • Proapoptotic activity of G3139 and VDAC blockage share dependencies on phosphorothioate modification, oligonucleotide length, and sequence independence.

Conclusions:

  • MOM permeability regulated by VDAC gating is crucial for mitochondrial function and apoptosis control.
  • VDAC plays a significant role in the initiation and regulation of apoptosis.

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