MAC inhibitors suppress mitochondrial apoptosis

Pablo M Peixoto1, Shin-Young Ryu, Agnes Bombrun

  • 1Department of Basic Sciences, New York University College of Dentistry, New York, NY 10010, USA.

The Biochemical Journal
|August 21, 2009
PubMed

Insights

Compounds that close the mitochondrial apoptosis-induced channel (MAC) can prevent cell death. These compounds effectively blocked cytochrome c release and halted apoptosis, indicating MAC is a potential therapeutic target.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Pharmacology

Background:

  • The mitochondrial apoptosis-induced channel (MAC) is crucial for intrinsic apoptosis, mediating cytochrome c release.
  • MAC opening is a key commitment step in programmed cell death.
  • Inhibiting MAC could represent a therapeutic strategy to prevent apoptosis.

Purpose of the Study:

  • To identify and characterize compounds that can directly close MAC.
  • To evaluate the efficacy of these compounds in suppressing apoptosis in cellular models.

Main Methods:

  • Recombinant Bax protein was used to assess compound efficacy in blocking fluorescein release from liposomes.
  • Compounds were tested for their ability to directly close MAC.
  • Apoptosis was induced in FL5.12 cells via IL-3 deprivation or staurosporine treatment.
  • Cytochrome c release and apoptotic markers were monitored.

Main Results:

  • Several compounds were identified that irreversibly closed MAC at low concentrations (IC50: 19–966 nM).
  • These compounds effectively inhibited cytochrome c release.
  • The tested compounds suppressed the onset of apoptotic markers induced by IL-3 deprivation or staurosporine.

Conclusions:

  • A direct link exists between MAC activity, cytochrome c release, and apoptotic cell death.
  • The mitochondrial apoptosis-induced channel (MAC) is a viable therapeutic target for preventing apoptosis.

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