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A Bax/Bak-independent mechanism of cytochrome c release

Takeshi Mizuta1, Shigeomi Shimizu, Yousuke Matsuoka

  • 1Laboratory of Molecular Genetics, Department of Medical Genetics, Osaka University Medical School, Osaka 565-0871, Japan.

The Journal of Biological Chemistry
|April 6, 2007
PubMed

Insights

Two distinct pathways trigger apoptosis: one relies on Bax and Bak proteins, while another, independent pathway involves serine proteases. This discovery reveals alternative routes for programmed cell death.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Bax and Bak are key pro-apoptotic proteins regulating mitochondrial outer membrane permeabilization and apoptosis.
  • Mice lacking Bax and Bak are resistant to apoptosis, suggesting their essential role in apoptotic signaling.
  • The precise mechanisms governing cytochrome c release and subsequent apoptosis are not fully elucidated.

Purpose of the Study:

  • To investigate alternative mechanisms of apoptosis induction independent of Bax and Bak.
  • To identify the molecular players involved in Bax/Bak-independent cytochrome c release and caspase activation.

Main Methods:

  • Utilized double-knock-out mouse embryonic fibroblasts lacking Bax and Bak.
  • Stimulated apoptosis using calcium ionophore A23187 and arachidonic acid (ArA).
  • Assessed cytochrome c release, caspase activation, and effects of serine protease inhibitors and Bcl-2 family proteins.

Main Results:

  • A23187/ArA induced cytochrome c release and caspase-dependent death in Bax/Bak-deficient cells, indicating alternative apoptotic pathways.
  • This death pathway was significantly inhibited by serine protease inhibitors but not by Bcl-2 overexpression or inhibition of mitochondrial permeability transition.
  • Identified a Bax/Bak-independent, serine protease-dependent mechanism of cytochrome c release and apoptosis.

Conclusions:

  • There are at least two distinct mechanisms for initiating apoptosis: a Bax/Bak-dependent pathway and a Bax/Bak-independent pathway.
  • The latter pathway relies on the activity of specific serine proteases for cytochrome c release and caspase activation.
  • These findings expand our understanding of the complex regulation of programmed cell death.

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