Mitochondrial targeting of tBid/Bax: a role for the TOM complex?
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.
Ott
M
M
Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Norberg
E
E
Zhivotovsky
B
B
Orrenius
S
S
D000595:Amino Acid Sequence; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D051028:bcl-2-Associated X Protein; D020169:Caspases