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Bid‐independent mitochondria activation in TNFalpha‐induced apoptosis and liver injury
Author(s) -
Ni HongMin,
Chen Xiaoyun,
Ding Wenxing,
Gao Wentao,
Yin XiaoMing
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a188-d
Subject(s) - mitochondrion , apoptosis , microbiology and biotechnology , tumor necrosis factor alpha , mitochondrial permeability transition pore , programmed cell death , reactive oxygen species , chemistry , signal transduction , biology , immunology , biochemistry
The death receptor apoptosis pathway is intimately connected with the mitochondria apoptosis pathway. Bid is a BH3‐only pro‐death Bcl‐2 family protein and is the major molecule linking the two pathways. The Bid‐mediated mitochondria activation occurs early and is responsible for the prompt progress of TNFalpha‐induced apoptosis. However, in both cultured cells and animal models of TNFalpha‐induced injury, a later phase Bid‐independent mitochondria 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 TNFalpha in the absence of p65relA can not 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 mitochondria activation. Inhibition of these events suppresses the TNFalpha‐induced mitochondria activation and apoptosis in bid‐deficient cells. These findings thus indicate that there are at least two sets of mechanisms of mitochondria activation upon TNFalpha stimulation. While the Bid‐mediated mechanism is rapid and potent, the Bid‐independent mechanism progresses gradually and involves multiple players. The critical involvement of Bid‐independent mitochondria activation in TNFalpha‐induced apoptosis demands the intervention of TNFalpha‐mediated tissue injury via multiple avenues.