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Molecular and Cellular Biology, January 2007, p. 541-553, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.01166-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Bid-Independent Mitochondrial Activation in Tumor Necrosis Factor Alpha-Induced Apoptosis and Liver Injury

Departments of Pathology,¹ Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,³ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China 200032,² Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612⁴

Received 28 June 2006/ Returned for modification 26 July 2006/ Accepted 25 October 2006

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-)-induced apoptosis. However, in both cultured cells and animal models of TNF--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- 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--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- 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 mitochondrial activation in TNF--induced apoptosis demands the intervention of TNF--mediated tissue injury via multiple avenues.

Published ahead of print on 13 November 2006.

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