HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 35, 36803-36808, August 27, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/35/36803    most recent M405297200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Soriano, M. E. Articles by Bernardi, P. Search for Related Content PubMed PubMed Citation Articles by Soriano, M. E. Articles by Bernardi, P. Social Bookmarking                      What's this?

Desensitization of the Permeability Transition Pore by Cyclosporin A Prevents Activation of the Mitochondrial Apoptotic Pathway and Liver Damage by Tumor Necrosis Factor-^*

Maria Eugenia Soriano, Luca Nicolosi¶, and Paolo Bernardi||**

From the Consiglio Nazionale delle Ricerche Institute of Neuroscience at the Department of Biomedical Sciences, University of Padova, Viale Giuseppe Colombo 3, I-35121 Padova, Italy and the ^||Venetian Institute of Molecular Medicine, Via Orus 2, I-35129 Padova, Italy

We studied the effects of cyclosporin A (CsA) administration 1) on the properties of the permeability transition pore (PTP) in mitochondria isolated from the liver and 2) on the susceptibility to hepatotoxicity induced by lipopolysaccharide of Escherichia coli (LPS) plus D-galactosamine (D-GalN) in rats. CsA exerted a marked PTP inhibition ex vivo, with an effect that peaked between 2 and 9 h of drug treatment and decayed with an apparent half-time of about 13 h. Administration of LPS plus D-GalN to naive rats caused the expected increased serum levels of tumor necrosis factor (TNF)-, liver inflammation with BID cleavage, activation of caspase 3, appearance of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive nuclei, and release of alanine aminotransferase and aspartate aminotransferase into the bloodstream. Treatment with CsA before or within 5 h of the administration of LPS plus D-GalN protected rats from hepatotoxicity despite the normal increase of serum TNF- and BID cleavage. These results indicate that CsA prevents the hepatotoxic effects of TNF- by blocking the mitochondrial proapoptotic pathway through inhibition of the PTP and provides a viable strategy for the treatment of liver diseases that depend on increased production and/or liver sensitization to TNF-.

Received for publication, May 12, 2004

^* This work was supported in part by Grants from the Associazione Italiana per la Ricerca sul Cancro and Telethon-Italy (to P. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^¶ Presented in partial fulfillment of the requirements for the Ph.D. degree in the School of Biosciences, Program in Cell Biology of the University of Padova.

^** To whom correspondence should be addressed. Fax: 39-049-827-6361; E-mail: bernardi{at}bio.unipd.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. Merlini, A. Angelin, T. Tiepolo, P. Braghetta, P. Sabatelli, A. Zamparelli, A. Ferlini, N. M. Maraldi, P. Bonaldo, and P. Bernardi Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies PNAS, April 1, 2008; 105(13): 5225 - 5229. [Abstract] [Full Text] [PDF]

				M. JUHASZOVA, S. WANG, D. B. ZOROV, H. BRADLEY NUSS, M. GLEICHMANN, M. P. MATTSON, and S. J. SOLLOTT The Identity and Regulation of the Mitochondrial Permeability Transition Pore: Where the Known Meets the Unknown Ann. N.Y. Acad. Sci., March 1, 2008; 1123(1): 197 - 212. [Abstract] [Full Text] [PDF]

				A. Wullaert, G. van Loo, K. Heyninck, and R. Beyaert Hepatic Tumor Necrosis Factor Signaling and Nuclear Factor-{kappa}B: Effects on Liver Homeostasis and Beyond Endocr. Rev., June 1, 2007; 28(4): 365 - 386. [Abstract] [Full Text] [PDF]

				A.-K. Yi, H. Yoon, J.-E. Park, B.-S. Kim, H. J. Kim, and A. Martinez-Hernandez CpG DNA-mediated Induction of Acute Liver Injury in D-Galactosamine-sensitized Mice: THE MITOCHONDRIAL APOPTOTIC PATHWAY-DEPENDENT DEATH OF HEPATOCYTES J. Biol. Chem., May 26, 2006; 281(21): 15001 - 15012. [Abstract] [Full Text] [PDF]

				F. Di Lisa and P. Bernardi Mitochondria and ischemia-reperfusion injury of the heart: Fixing a hole Cardiovasc Res, May 1, 2006; 70(2): 191 - 199. [Abstract] [Full Text] [PDF]

				E. Milanesi, P. Costantini, A. Gambalunga, R. Colonna, V. Petronilli, A. Cabrelle, G. Semenzato, A. M. Cesura, E. Pinard, and P. Bernardi The Mitochondrial Effects of Small Organic Ligands of BCL-2: SENSITIZATION OF BCL-2-OVEREXPRESSING CELLS TO APOPTOSIS BY A PYRIMIDINE-2,4,6-TRIONE DERIVATIVE J. Biol. Chem., April 14, 2006; 281(15): 10066 - 10072. [Abstract] [Full Text] [PDF]

				S. Y. Cheranov and J. H. Jaggar TNF-{alpha} dilates cerebral arteries via NAD(P)H oxidase-dependent Ca2+ spark activation Am J Physiol Cell Physiol, April 1, 2006; 290(4): C964 - C971. [Abstract] [Full Text] [PDF]

				M. Cebecauer, P. Guillaume, P. Hozak, S. Mark, H. Everett, P. Schneider, and I. F. Luescher Soluble MHC-Peptide Complexes Induce Rapid Death of CD8+ CTL J. Immunol., June 1, 2005; 174(11): 6809 - 6819. [Abstract] [Full Text] [PDF]

				E. Basso, L. Fante, J. Fowlkes, V. Petronilli, M. A. Forte, and P. Bernardi Properties of the Permeability Transition Pore in Mitochondria Devoid of Cyclophilin D J. Biol. Chem., May 13, 2005; 280(19): 18558 - 18561. [Abstract] [Full Text] [PDF]