¹Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden

Correspondence: B Zhivotovsky, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden. Tel: +46 8 524 875 88; Fax: +46 8 32 90 41; E-mail: boris.zhivotovsky@ki.se

²These authors contributed equally to this work

³Current address: Molecular Cell Biology, Faculty of Biology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany

Received 18 March 2009; Revised 24 April 2009; Accepted 24 April 2009; Published online 12 June 2009.

Abstract

The release of pro-apoptotic proteins from the mitochondria is a key event in cell death signaling that is regulated by Bcl-2 family proteins. For example, cleavage of the BH3-only protein, Bid, by multiple proteases leads to the formation of truncated Bid that, in turn, promotes the insertion/oligomerization of Bax into the mitochondrial outer membrane, resulting in pore formation and the release of proteins residing in the intermembrane space. Bax, a monomeric protein in the cytosol is targeted to the mitochondria by a yet unknown mechanism. Several proteins of the outer mitochondrial membrane have been proposed to act as receptors for Bax, among them the voltage-dependent anion channel, VDAC, and the mitochondrial protein translocase of the outer membrane, the TOM complex. Alternatively, the unique mitochondrial phospholipid, cardiolipin, has been ascribed a similar function. Here, we review recent work on the mechanisms of activation and the targeting of Bax to the mitochondria and discuss the advantages and limitations of the methods used to study this process.