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Originally published In Press as doi:10.1074/jbc.M204951200 on May 31, 2002

J. Biol. Chem., Vol. 277, Issue 32, 29181-29186, August 9, 2002
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Calpain and Mitochondria in Ischemia/Reperfusion Injury*

Min ChenDagger §, Dong-Jun WonDagger , Stan Krajewski, and Roberta A. GottliebDagger ||

From Dagger  The Scripps Research Institute and  The Burnham Institute, La Jolla, California 92037

Studies of ischemia/reperfusion (I/R) injury and preconditioning have shown that ion homeostasis, particularly calcium homeostasis, is critical to limiting tissue damage. However, the relationship between ion homeostasis and specific cell death pathways has not been investigated in the context of I/R. Previously we reported that calpain cleaved Bid in the absence of detectable caspase activation (1). In this study, we have shown that an inhibitor of the sodium/hydrogen exchanger prevented calpain activation after I/R. Calpain inhibitors prevented cleavage of Bid as well as the downstream indices of cell death, including DNA strand breaks, creatine kinase (CK) release, and infarction measured by triphenyl tetrazolium chloride (TTC) staining. In contrast, the broad spectrum caspase inhibitor IDN6734 was not protective in this model. To ascertain whether mitochondrial dysfunction downstream of these events was a required step, we utilized a peptide corresponding to residues 4-23 of Bcl-xL conjugated to the protein transduction domain of HIV TAT (TAT-BH4), which has been shown to protect mitochondria against Ca2+-induced Delta Psi m loss (2). TAT-BH4 attenuated CK release and loss of TTC staining, demonstrating the role of mitochondria and a pro-apoptotic Bcl-2 family member in the process leading to cell death. We propose the following pathway. (i) Reperfusion results in sodium influx followed by calcium accumulation. (ii) This leads to calpain activation, which in turn leads to Bid cleavage. (iii) Bid targets the mitochondria, causing dysfunction and release of pro-apoptotic factors, resulting in DNA fragmentation and death of the cell. Ischemia/reperfusion initiates a cell death pathway that is independent of caspases but requires calpain and mitochondrial dysfunction.

* This work was supported by National Institutes of Health Grants HL 60590 (to R. A. G.) and NS 36821 (to S. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of an American Heart Association fellowship.

|| To whom correspondence should be addressed: Dept. of Molecular and Experimental Medicine, MEM220, The Scripps Research Inst., 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-9165; Fax: 858-784-8389; E-mail: robbieg@scripps.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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