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Bid activates multiple mitochondrial apoptotic mechanisms in primary hepatocytes after death receptor engagement.

Abstract：

BACKGROUND & AIMS:Activation of Fas or tumor necrosis factor receptor 1 (TNF-R1) on hepatocytes leads to apoptosis, which requires mitochondria activation. The pro-death Bcl-2 family protein, Bid, mediates this pathway by inducing mitochondrial releases of cytochrome c and other apoptotic factors. How Bid activates mitochondria has been studied in vitro with isolated mitochondria. We intended to study the mechanisms in intact hepatocytes so that findings could be made in a proper cellular context and would be more physiologically relevant. METHODS:Hepatocytes were isolated from wild-type and bid-deficient mice and treated with anti-Fas or TNF-alpha. Mechanisms of mitochondria activation were dissected with genetic, biochemical, and morphologic approaches. RESULTS:bid-deficient hepatocytes were much more resistant to apoptosis. Bid was required for permeability transition and mitochondria depolarization in addition to the previously defined release of cytochrome c. Permeability transition inhibitors cyclosporin A and aristolochic acid could inhibit mitochondria activation effectively, but not as much as the deletion of the bid gene, and they could not inhibit Bak oligomerization. In addition, mitochondria depolarization also could be induced by caspases, whose activation was mainly dependent on Bid. CONCLUSIONS:Bid may activate mitochondria by 2 mechanisms, one is related to permeability transition and the other is related to Bak oligomerization. Bid can further affect mitochondria potentials by indirectly regulating caspase activity. This in vivo study provides novel findings not previously disclosed by in vitro studies, and indicates the importance of several mechanisms in contributing Bid-mediated mitochondria dysfunction that could be potential cellular targets of intervention.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Zhao Y,Ding WX,Qian T,Watkins S,Lemasters JJ,Yin XM

doi

10.1016/s0016-5085(03)01066-7

keywords:

subject

Has Abstract

pub_date

2003-09-01 00:00:00

pages

854-67

issue

eissn

0016-5085

issn

1528-0012

pii

S0016508503010667

journal_volume

125

pub_type

杂志文章

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Bid activates multiple mitochondrial apoptotic mechanisms in primary hepatocytes after death receptor engagement.