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Molecular and Cellular Biology, November 1998, p. 6353-6364, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Mitochondrial Permeability Transition Is Required for Tumor Necrosis Factor Alpha-Mediated Apoptosis and Cytochrome c Release

Cynthia A. Bradham,1 Ting Qian,3 Konrad Streetz,4 Christian Trautwein,4 David A. Brenner,1,2,* and John J. Lemasters3

Departments of Medicine,1 Biochemistry & Biophysics,2 and Cell Biology & Anatomy,3 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, and Department of Gastroenterology and Hepatology, Mediziniche Hochschule Hannover, Hannover, Germany4

Received 13 April 1998/Returned for modification 26 May 1998/Accepted 11 August 1998

This study assesses the controversial role of the mitochondrial permeability transition (MPT) in apoptosis. In primary rat hepatocytes expressing an Ikappa B superrepressor, tumor necrosis factor alpha (TNFalpha ) induced apoptosis as shown by nuclear morphology, DNA ladder formation, and caspase 3 activation. Confocal microscopy showed that TNFalpha induced onset of the MPT and mitochondrial depolarization beginning 9 h after TNFalpha treatment. Initially, depolarization and the MPT occurred in only a subset of mitochondria; however, by 12 h after TNFalpha treatment, virtually all mitochondria were affected. Cyclosporin A (CsA), an inhibitor of the MPT, blocked TNFalpha -mediated apoptosis and cytochrome c release. Caspase 3 activation, cytochrome c release, and apoptotic nuclear morphological changes were induced after onset of the MPT and were prevented by CsA. Depolarization and onset of the MPT were blocked in hepatocytes expressing Delta FADD, a dominant negative mutant of Fas-associated protein with death domain (FADD), or crmA, a natural serpin inhibitor of caspases. In contrast, Asp-Glu-Val-Asp-cho, an inhibitor of caspase 3, did not block depolarization or onset of the MPT induced by TNFalpha , although it inhibited cell death completely. In conclusion, the MPT is an essential component in the signaling pathway for TNFalpha -induced apoptosis in hepatocytes which is required for both cytochrome c release and cell death and functions downstream of FADD and crmA but upstream of caspase 3.

* Corresponding author. Mailing address: 326 Burnett-Womack C.B. 7080, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 966-0650. Fax: (919) 966-7468. E-mail: dab{at}med.unc.edu.

Molecular and Cellular Biology, November 1998, p. 6353-6364, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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