Bid-independent mitochondrial activation in tumor necrosis factor alpha-induced apoptosis and liver injury

Xiaoyun Chen, Wen Xing Ding, Hong Min Ni, Wentao Gao, Ying Hong Shi, Andrea A. Gambotto, Jia Fan, Amer A. Beg, Xiao-Ming Yin

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

The death receptor apoptosis pathway is intimately connected with the mitochondrial apoptosis pathway. Bid is a BH3-only pro-death Bcl-2 family protein and is the major molecule linking the two pathways, Bid-mediated mitochondrial activation occurs early and is responsible for the prompt progress of tumor necrosis factor alpha (TNF-α)-induced apoptosis. However, in both cultured cells and animal models of TNF-α-induced injury, later-phase Bid-independent mitochondrial activation could be demonstrated. Consequently, bid-deficient mice are still susceptible to endotoxin-induced liver injury and mortality. Notably, embryonic hepatocyte apoptosis and lethality caused by TNF-α in the absence of p65relA cannot be rescued by the simultaneous deletion of bid. Further studies indicate that multiple mechanisms including reactive oxygen species, JNK, and permeability transition are critically involved in Bid-independent mitochondrial activation. Inhibition of these events suppresses TNF-α-induced mitochondrial activation and apoptosis in bid-deficient cells. These findings thus indicate that there are at least two sets of mechanisms of mitochondrial activation upon TNF-α stimulation. While the Bid-mediated mechanism is rapid and potent, the Bid-independent mechanism progresses gradually and involves multiple players. The critical involvement of lid-independent mitochondrial activation in TNF-α-induced apoptosis demands the intervention of TNF-α-mediated tissue injury via multiple avenues.

Original languageEnglish (US)
Pages (from-to)541-553
Number of pages13
JournalMolecular and Cellular Biology
Volume27
Issue number2
DOIs
StatePublished - Jan 2007
Externally publishedYes

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Tumor Necrosis Factor-alpha
Apoptosis
Liver
Wounds and Injuries
Death Domain Receptors
Multiple Trauma
Endotoxins
Hepatocytes
Cultured Cells
Permeability
Reactive Oxygen Species
Animal Models
Mortality
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Bid-independent mitochondrial activation in tumor necrosis factor alpha-induced apoptosis and liver injury. / Chen, Xiaoyun; Ding, Wen Xing; Ni, Hong Min; Gao, Wentao; Shi, Ying Hong; Gambotto, Andrea A.; Fan, Jia; Beg, Amer A.; Yin, Xiao-Ming.

In: Molecular and Cellular Biology, Vol. 27, No. 2, 01.2007, p. 541-553.

Research output: Contribution to journalArticle

Chen, Xiaoyun ; Ding, Wen Xing ; Ni, Hong Min ; Gao, Wentao ; Shi, Ying Hong ; Gambotto, Andrea A. ; Fan, Jia ; Beg, Amer A. ; Yin, Xiao-Ming. / Bid-independent mitochondrial activation in tumor necrosis factor alpha-induced apoptosis and liver injury. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 2. pp. 541-553.
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