Activation of Pro-death Bcl-2 Family Proteins and Mitochondria Apoptosis Pathway in Tumor Necrosis Factor-α-induced Liver Injury

Yongge Zhao, Shuchen Li, Erin E. Childs, Diane K. Kuharsky, Xiao-Ming Yin

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Tumor necrosis factor-α (TNFα)-induced cytotoxicity contributes to the pathogenesis in inflammatory and immune responses. Here, we studied the role of pro-death Bcl-2 family proteins and the mitochondria apoptosis pathway in the development of TNFα-induced hepatic injury during endotoxemia. After treating mice with lipopolysaccharide or TNFα in the presence of D-galactosamine, Bid was cleaved and translocated to mitochondria in hepatocytes. Independently, Bax was also activated by the death receptor engagement and translocated to mitochondria. However, its subsequent insertion into the mitochondrial membrane depends on Bid. Nevertheless, Bid was required, but Bax could be dispensed for the mitochondrial release of cytochrome c from mitochondria, suggesting that Bid could activate additional downstream molecules other than Bax. The lack of this Bid-dependent mitochondria activation and cytochrome c release in the bid-deficient mice was responsible for the significantly delayed effector caspase activation and hepatocyte injury upon endotoxin treatment, culminating in a prolonged survival of the bid-deficient mice. Additional genetic factor(s) could further modify the dependence of TNFα toxicity on the mitochondria pathway as the bid-deficient 129/SvJ mice manifested an even higher resistance than the same type of mice in C57BL/6 background. The functional significance of the mitochondria apoptosis pathway was thus elucidated in the TNFα-mediated pathogenesis in vivo.

Original languageEnglish (US)
Pages (from-to)27432-27440
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number29
DOIs
StatePublished - Jul 20 2001
Externally publishedYes

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Mitochondria
Liver
Tumor Necrosis Factor-alpha
Chemical activation
Apoptosis
Wounds and Injuries
Proteins
Cytochromes c
Hepatocytes
Effector Caspases
129 Strain Mouse
Galactosamine
Death Domain Receptors
Endotoxemia
Mitochondrial Membranes
Cytotoxicity
Inbred C57BL Mouse
Endotoxins
Toxicity
Lipopolysaccharides

ASJC Scopus subject areas

  • Biochemistry

Cite this

Activation of Pro-death Bcl-2 Family Proteins and Mitochondria Apoptosis Pathway in Tumor Necrosis Factor-α-induced Liver Injury. / Zhao, Yongge; Li, Shuchen; Childs, Erin E.; Kuharsky, Diane K.; Yin, Xiao-Ming.

In: Journal of Biological Chemistry, Vol. 276, No. 29, 20.07.2001, p. 27432-27440.

Research output: Contribution to journalArticle

Zhao, Yongge ; Li, Shuchen ; Childs, Erin E. ; Kuharsky, Diane K. ; Yin, Xiao-Ming. / Activation of Pro-death Bcl-2 Family Proteins and Mitochondria Apoptosis Pathway in Tumor Necrosis Factor-α-induced Liver Injury. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 29. pp. 27432-27440.
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