1. ¹INSERM U601, France
2. ²Université de Nantes, Faculté de Médecine, Nantes, Cedex, France
3. ³Department of Biochemistry, University of Washington, Seattle, WA, USA
4. ⁴Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
5. ⁵CNRS UMR 5095, Université Bordeaux 2, Bordeaux, France

Correspondence: FM Vallette, IFR 26, UMR601 INSERM, Université de Nantes, Faculté de Médecine, 9 Quai Moncousu F-44035, Nantes Cedex 01, France. Tel: +33 240084081; Fax: +33 240084082; E-mail: francois.vallette@univ-nantes.fr

⁶These two authors contributed equally to this work.

Received 12 April 2006; Revised 4 September 2006; Accepted 26 September 2006; Published online 10 November 2006.

Abstract

The association of Bax with mitochondria is an essential step in the implementation of apoptosis. By using a bacterial two-hybrid assay and crosslinking strategies, we have identified TOM22, a component of the translocase of the outer mitochondrial membrane (TOM), as a mitochondrial receptor of Bax. Peptide mapping showed that the interaction of Bax with TOM22 involved the first alpha helix of Bax and possibly two central alpha helices, which are homologous to the pore forming domains of some toxins. Antibodies directed against TOM22 or an antisense knockdown of the expression of TOM22 specifically inhibited the association of Bax with mitochondria and prevented Bax-dependent apoptosis. In yeast, a haploid strain for TOM22 exhibited a decreased expression of TOM22 and mitochondrial association of ectopically expressed human Bax. Our data provide a new perspective on the mechanism of association of Bax with mitochondria as it involves a classical import pathway.