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Phosphorothioate oligonucleotides reduce mitochondrial outer membrane permeability to ADP

Wenzhi Tan1, Johnathan C Lai, Paul Miller

  • 1Department of Biology, University of Maryland, College Park, MD 20742, USA.

American Journal of Physiology. Cell Physiology
|December 1, 2006
PubMed

Insights

G3139, a novel antisense agent, triggers cancer cell death by blocking mitochondrial outer membrane permeability. This action, mediated by voltage-dependent anion-selective channels (VDAC), occurs early in apoptosis and is independent of Bcl-2.

Area of Science:

  • Mitochondrial biology
  • Cancer cell death pathways
  • Oligonucleotide therapeutics

Background:

  • Antisense phosphorothioate oligodeoxynucleotides like G3139 induce apoptosis in cancer cells.
  • The mechanism appears independent of Bcl-2 downregulation.
  • G3139's interaction with mitochondrial voltage-dependent anion-selective channels (VDAC) is hypothesized.

Purpose of the Study:

  • To investigate the mechanism of G3139-induced apoptosis.
  • To determine if G3139 interacts with VDAC to alter mitochondrial function.
  • To establish the role of VDAC in G3139's apoptotic effects.

Main Methods:

  • Assessing G3139's effect on mitochondrial outer membrane permeability to ADP.
  • Measuring inhibition constants (K(i)) for G3139's interaction with VDAC.
  • Evaluating the impact of G3139 on other mitochondrial respiration components.
  • Comparing G3139's effects with other phosphorothioate oligonucleotides.

Main Results:

  • G3139 significantly reduces mitochondrial outer membrane permeability to ADP (K(i) 0.2-0.5 microM).
  • This effect is attributed to VDAC closure, strengthening the initial hypothesis.
  • Mitochondrial respiration is unaffected at low G3139 concentrations but inhibited at higher levels.
  • Phosphorothioate oligonucleotides, particularly those with specific lengths and linkages, induce VDAC closure.

Conclusions:

  • G3139 acts early in the apoptotic cascade by modulating VDAC function and reducing mitochondrial outer membrane permeability.
  • VDAC closure by G3139 is a key mechanism preceding cytochrome c release.
  • Phosphorothioate oligonucleotides are identified as specific tools for restricting mitochondrial outer membrane permeability.

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