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Bid activates multiple mitochondrial apoptotic mechanisms in primary hepatocytes after death receptor engagement

Yongge Zhao1, Wen-Xing Ding, Ting Qian

  • 1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.

Gastroenterology
|September 2, 2003
PubMed
Abstract

Insights

Bid protein is crucial for hepatocyte apoptosis by activating mitochondria through permeability transition and Bak oligomerization. This study reveals new in vivo mechanisms for Bid-mediated mitochondrial dysfunction.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Hepatocyte apoptosis is triggered by Fas or TNF-R1 activation, requiring mitochondrial involvement.
  • The pro-apoptotic protein Bid mediates this pathway by initiating the release of cytochrome c from mitochondria.
  • Previous studies on Bid-mediated mitochondrial activation were limited to in vitro systems.

Purpose of the Study:

  • To investigate the mechanisms of Bid-induced mitochondrial activation in intact hepatocytes for greater physiological relevance.
  • To elucidate the role of Bid in hepatocyte apoptosis within a cellular context.

Main Methods:

  • Isolation of hepatocytes from wild-type and bid-deficient mice.
  • Treatment of hepatocytes with anti-Fas or TNF-alpha.
  • Dissection of mitochondrial activation mechanisms using genetic, biochemical, and morphological approaches.

Main Results:

  • Bid-deficient hepatocytes exhibited significantly increased resistance to apoptosis.
  • Bid was essential for mitochondrial permeability transition and depolarization, beyond cytochrome c release.
  • Inhibitors of permeability transition partially blocked mitochondrial activation and did not affect Bak oligomerization.
  • Caspase activation, dependent on Bid, also contributed to mitochondrial depolarization.

Conclusions:

  • Bid activates mitochondria via two distinct pathways: permeability transition and Bak oligomerization.
  • Bid indirectly influences mitochondrial membrane potential through regulation of caspase activity.
  • This in vivo study identified novel mechanisms of Bid-mediated mitochondrial dysfunction, highlighting potential therapeutic targets.

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