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Processed caspase-2 can induce mitochondria-mediated apoptosis independently of its enzymatic activity

John D Robertson1, Vladimir Gogvadze, Andrey Kropotov

  • 1Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.

EMBO Reports
|May 22, 2004
PubMed

Insights

Caspase-2 processing, not its catalytic activity, triggers cytochrome c release from mitochondria. This finding clarifies caspase-2

Area of Science:

  • Cellular Biology
  • Biochemistry
  • Molecular Biology

Background:

  • The precise mechanism of caspase-2 in apoptosis execution is not fully understood.
  • Caspase-2 activation by DNA-damaging agents suggests a role in the mitochondrial apoptotic pathway.

Purpose of the Study:

  • To elucidate the role of processed caspase-2 in initiating mitochondrial apoptosis.
  • To determine if caspase-2's proteolytic activity is essential for its mitochondrial function.

Main Methods:

  • Assessing mitochondrial release of apoptotic factors (cytochrome c, Smac/DIABLO, AIF).
  • Investigating the involvement of Bcl-2 family proteins (Bax, Bak, Bcl-2).
  • Evaluating mitochondrial respiration and respiratory control ratio.
  • Utilizing inactivation experiments to test the requirement of caspase-2's catalytic activity.

Main Results:

  • Fully processed caspase-2 induces mitochondrial release of cytochrome c and Smac/DIABLO, independent of Bax, Bak, and Bcl-2.
  • Caspase-2's proteolytic activity is not required for this mitochondrial effect.
  • Processed caspase-2 uncouples mitochondrial respiration, decreasing state 4 respiration and the respiratory control ratio.

Conclusions:

  • Caspase-2 directly engages the mitochondrial apoptotic pathway.
  • The processing of caspase-2 zymogen, not its catalytic activity, is crucial for initiating mitochondrial apoptosis.
  • Caspase-2 possesses a unique, non-proteolytic function in regulating mitochondrial apoptotic signaling.

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