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