Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 276, Issue 29, Pages 27432-27440Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M102465200
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- NCI NIH HHS [R01 CA83817, K01 CA74885] Funding Source: Medline
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Tumor-necrosis factor-alpha (TNF alpha)-induced cytotoxicity contributes to the pathogenesis in inflammatory and immune responses. Here, we studied the role of prodeath Bcl-2 family proteins and the mitochondria apoptosis pathway in the development of TNF alpha -induced hepatic injury during endotoxemia, after treating mice with lipopolysaccharide or TNF alpha 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 fax 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 TNF alpha 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 TNF alpha -mediated pathogenesis in vivo.
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