Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes

Wen Xing Ding, Hong Min Ni, Daniell DiFrancesca, Donna B. Stolz, Xiao-Ming Yin

Research output: Contribution to journalArticle

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Abstract

Activation of tumor necrosis factor receptor 1 or Fas leads to the generation of reactive oxygen species, which are important to the cytotoxic effects of tumor necrosis factor α (TNF-α) or Fas ligand. However, how these radicals are generated following receptor ligation is not clear. Using primary hepatocytes, we found that TNF-α or anti-Fas antibody-induced burst of oxygen radicals was mainly derived from the mitochondria. We discovered that Bid-a pro-death Bcl-2 family protein activated by ligated death receptors-was the main intracellular molecule signaling the generation of the radicals by targeting to the mitochondria and that the majority of oxygen radical production was dependent on Bid. Reactive oxygen species contributed to cell death and caspase activation by promoting FLICE-inhibitory protein degradation and mitochondrial release of cytochrome c. For the latter part, the oxygen radicals did not affect Bak oligomerization but instead promoted mitochondrial cristae reorganization and membrane lipid peroxidation. Antioxidants could reverse these changes and therefore protect against TNF-α or anti-Fas-induced apoptosis. In conclusion, our studies established the signaling pathway from death receptor engagement to oxygen radical generation and determined the mechanism by which reactive oxygen species contributed to hepatocyte apoptosis following death receptor activation.

Original languageEnglish (US)
Pages (from-to)403-413
Number of pages11
JournalHepatology
Volume40
Issue number2
DOIs
StatePublished - Aug 2004
Externally publishedYes

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Death Domain Receptors
Hepatocytes
Reactive Oxygen Species
Apoptosis
Tumor Necrosis Factor-alpha
Mitochondria
CASP8 and FADD-Like Apoptosis Regulating Protein
Fas Ligand Protein
Tumor Necrosis Factor Receptors
Membrane Lipids
Caspases
Cytochromes c
Lipid Peroxidation
Proteolysis
Ligation
Anti-Idiotypic Antibodies
Cell Death
Antioxidants

ASJC Scopus subject areas

  • Hepatology

Cite this

Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes. / Ding, Wen Xing; Ni, Hong Min; DiFrancesca, Daniell; Stolz, Donna B.; Yin, Xiao-Ming.

In: Hepatology, Vol. 40, No. 2, 08.2004, p. 403-413.

Research output: Contribution to journalArticle

Ding, Wen Xing ; Ni, Hong Min ; DiFrancesca, Daniell ; Stolz, Donna B. ; Yin, Xiao-Ming. / Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes. In: Hepatology. 2004 ; Vol. 40, No. 2. pp. 403-413.
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