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

Abstract

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 IkappaBalpha-NF-kappaB complex into mitochondria, with a coincident decrease in nuclear NF-kappaB DNA binding activity. In this situation, NF-kappaB 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 IkappaBalpha-NF-kappaB recruitment or changes in NF-kappaB activity. Thus, we propose that the mitochondrial recruitment of NF-kappaB observed following ANT1 overexpression has an important role in ANT1 proapoptotic activity.