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J. Biol. Chem., Vol. 279, Issue 37, 38415-38423, September 10, 2004

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Recruitment of NF-B into Mitochondria Is Involved in Adenine Nucleotide Translocase 1 (ANT1)-induced Apoptosis^*

Monica Zamora, Claudia Meroño, Octavi Viñas, and Teresa Mampel

From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Diagonal 645, 08028 Barcelona, Spain

Overexpression of adenine nucleotide translocase-1 (ANT1) is known to induce apoptosis (Bauer, M. K., Schubert, A., Rocks, O., and Grimm, S. (1999) J. Cell Biol. 147, 1493–1501), but the mechanisms involved remain unclear. In this study we show that ANT1 overexpression results in a recruitment of the IB-NF-B complex into mitochondria, with a coincident decrease in nuclear NF-B DNA binding activity. In this situation, NF-B transcriptionally regulated genes with antiapoptotic activity, such as Bcl-XL, MnSOD2, and c-IAP2, are down-regulated, and consequently, cells are sensitized to apoptosis. Accordingly, co-expression of p65 partially interferes with the proapoptotic effect of ANT1 overexpression. Despite the high identity of the two isoforms, overexpression of ANT2 does not exert an apoptotic effect; this lack of apoptotic activity is correlated with the absence of mitochondrial IB-NF-B recruitment or changes in NF-B activity. Thus, we propose that the mitochondrial recruitment of NF-B observed following ANT1 overexpression has an important role in ANT1 proapoptotic activity.

Received for publication, May 4, 2004 , and in revised form, June 21, 2004.

^* This work was supported by Grant PM1999-0171 from the Ministerio de Ciencia y Tecnologia (Spain) and by Grant 2001-SGR-00117 from the Generalitat de Catalunya (Spain). 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.

Both authors contributed equally to this work and share senior co-authorship.

To whom correspondence should be addressed. Tel.: 34-934021520; Fax: 34-934021559; E-mail: tmampel{at}ub.edu.

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