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The cardiolipin-binding domain of Bid affects mitochondrial respiration and enhances cytochrome c release

J Liu1, A Weiss, D Durrant

  • 1Huntsman Cancer Institute, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA.

Apoptosis : an International Journal on Programmed Cell Death
|August 18, 2004
PubMed

Insights

The cardiolipin-binding domain (CBD) of Bid targets mitochondria and induces apoptosis by interacting with cardiolipin. This domain is crucial for Bid-mediated apoptosis, affecting cytochrome c release and mitochondrial respiration.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Bid is a crucial protein in the apoptosis pathway, activated by caspase 8 cleavage into truncated Bid (tBid).
  • tBid translocates to mitochondria, where it interacts with cardiolipin, initiating apoptotic signaling.
  • The cardiolipin-binding domain (CBD) of Bid (amino acids 103-162) is responsible for this mitochondrial targeting.

Purpose of the Study:

  • To investigate the role and mechanism of the cardiolipin-binding domain (CBD) of Bid in apoptosis.
  • To determine if CBD alone can induce apoptosis and how it interacts with cardiolipin.

Main Methods:

  • Recombinant CBD and a mutant tBid (tBid(G94E)) were used to study cardiolipin binding.
  • [(3)H]cardiolipin was used to quantify binding affinities.
  • Cytochrome c release from isolated mitochondria and in Bax-deficient cells was measured.
  • The effect of CBD on mitochondrial respiration was assessed.

Main Results:

  • Recombinant CBD demonstrated cardiolipin-binding capabilities comparable to tBid.
  • CBD induced cytochrome c release from isolated mitochondria, though less potently than tBid.
  • Free cardiolipin inhibited CBD-induced cytochrome c release, suggesting interference with cardiolipin-cytochrome c interactions.
  • CBD induced cytochrome c release in Bax-deficient cells and suppressed mitochondrial respiration by directly interfering with cardiolipin.

Conclusions:

  • The cardiolipin-binding domain (CBD) of Bid is functionally important for tBid-induced apoptosis.
  • CBD's interaction with cardiolipin is critical for initiating cytochrome c release and impairing mitochondrial function.
  • CBD's mechanism involves direct interference with mitochondrial cardiolipin, impacting both apoptosis and oxidative phosphorylation.

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